Open Access

Neutrophil plasticity enables the development of pathological microenvironments: implications for cystic fibrosis airway disease

Molecular and Cellular Pediatrics20163:38

DOI: 10.1186/s40348-016-0066-2

Received: 26 September 2016

Accepted: 4 November 2016

Published: 5 December 2016

Abstract

Introduction

The pathological course of several chronic inflammatory diseases, including cystic fibrosis, chronic obstructive pulmonary disease, and rheumatoid arthritis, features an aberrant innate immune response dominated by neutrophils. In cystic fibrosis, neutrophil burden and activity of neutrophil elastase in the extracellular fluid have been identified as strong predictors of lung disease severity.

Review

Although neutrophils are generally considered to be rigid, pre-programmed effector leukocytes, recent studies suggest extensive plasticity in how neutrophil functions unfold upon recruitment to peripheral tissues, and how they choose their ultimate fate. Indeed, upon migration to cystic fibrosis airways, neutrophils display dysregulated lifespan, metabolic activation, and altered effector and regulatory functions, consistent with profound adaptation and phenotypic reprogramming. Licensed by signals present in cystic fibrosis airway microenvironment to survive and develop these novel functions, neutrophils orchestrate, in partnership with the epithelium and with the resident microbiota, the evolution of a pathological microenvironment. This microenvironment is defined by altered proteolytic, redox, and metabolic balance and the presence of stable luminal structures in which neutrophils and microbes coexist.

Conclusions

The elucidation of molecular mechanisms driving neutrophil plasticity in vivo will open new treatment opportunities designed to modulate, rather than block, the crucial adaptive functions fulfilled by neutrophils. This review aims to outline emerging mechanisms of neutrophil plasticity and their participation in the building of pathological microenvironments in the context of cystic fibrosis and other diseases with similar features.

Keywords

Amino acids Exocytosis Glucose Inflammation Immunometabolism Reprogramming

Introduction

Neutrophils constitute the first line of defense against infection in most organisms. It is estimated that the human body produces 109 neutrophils/kg/day, making them the most abundant leukocytes in bone marrow (BM) and blood. Neutrophils play an important role in protective immunity, which explains the severe pathologies arising upon hereditary or acquired impairment of neutrophil number and function. Blood neutrophils are conventionally thought of as terminally differentiated cells with little license to adapt to conditions within tissues beyond their ability to kill pathogens intracellularly by phagocytosis, or extracellularly by degranulation or release of DNA-based neutrophil extracellular traps (or NETs) in a recently discovered process dubbed “NETosis”.

However, in the context of cystic fibrosis (CF) lung disease, neutrophils show complex properties, detailed below, that come in stark contrast with the rigid pre-programmed phenotype generally expected of them and instead emphasize their inherent plasticity. CF is a hereditary, recessive disease that predominately impacts individuals of European ancestry. According to the World Health Organization, its incidence varies between 1 in 2000 and 1 in 3500 newborns worldwide. The gene mutated in CF patients encodes the CF transmembrane conductance regulator (CFTR), an ATP-binding cassette family member that regulates the movement of anions, such as chloride, bicarbonate, thiocyanate, and glutathione (GSH), across the plasma membrane [1, 2]. So far, more than 1800 disease-causing mutations have been identified among CF patients, with the F508Del mutation being the most frequent (~70% of mutated alleles) [3, 4]. Digestive enzyme supplements have noticeably increased CF patients’ lifespan and shifted the main cause of morbidity from nutrient malabsorption due to pancreatic failure to chronic lung disease [5].

Impaired mucociliary clearance, bacterial infection, and neutrophilic inflammation are all hallmarks of CF lung disease [6, 7]. Among those, neutrophil burden and extracellular activity of the protease neutrophil elastase (NE) in CF airway fluid correlate best with disease progression in CF patients, from infancy to adulthood [8]. The role of neutrophil inflammation in CF pathophysiology has been exhaustively reviewed elsewhere [911]. Recent reviews detail the putative role of other immune cells, such as macrophages, in CF lung disease [1214]. In the present review, our goal is to direct the attention of the reader to the phenotypic reprogramming process that neutrophils undergo in the context of CF lung disease, and explore potential mechanisms and treatment opportunities afforded by this newly discovered process. Importantly, this new view of neutrophils, which we illustrate in the context of CF, echoes recent findings made in the context of acute infection and sepsis, as well as other chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), and systemic lupus erythematosus, as well as cancer, where neutrophils also display new, complex phenotypes and effector functions [15].

Review

Neutrophil plasticity in CF lung disease: emergent mechanisms

Lifespan and aging

Pulse-chase experiments were conducted recently to measure the lifespan of human neutrophils in blood. Models accounting for the loss of the deuterium label led to estimates of a few hours to up to 5 days [16, 17]. Although their exact lifespan is debated, it is of general consensus that neutrophils leave the BM with a default pro-apoptotic program that can be inhibited by stimuli received upon migration to peripheral tissues [18, 19]. In CF, there is no experimental data on the precise lifespan of neutrophils in the lung, and this subject remains debated. On the one hand, the hostile environment of the CF lung, and notably the presence of bacterial toxins, could induce rapid necrosis of incoming neutrophils [2022]. On the other hand, neutrophil lifespan may be extended by several factors, such as pro-survival signals from neutrophils, as well as exogenous drugs, and epithelial and microbial inflammatory mediators and metabolites. For example, Sutanto et al. [23] showed that primary epithelial cells from CF infants not only secrete higher levels of inflammatory mediators compared to their healthy counterparts at baseline but also display an increased production of interleukin-8 (IL-8) in response to human rhinovirus infection. In addition to being a strong chemoattractant [24], IL-8 can delay neutrophil apoptosis [25]. Thus, the CF airway epithelium may contribute to a higher lifespan of neutrophils recruited to the lumen.

To achieve a balanced number of neutrophils in blood, the high daily rate of release of mature young neutrophils into the bloodstream is compensated by the clearance of senescent neutrophils from it. Circadian rhythm is a major factor influencing hematopoiesis in general and neutrophil turnover in particular [2628]. From a phenotypic standpoint, developing neutrophils in the bone marrow (BM) express the chemokine receptor CXCR4, which acts as a retention signal by binding to its cognate ligand CXCL12 on stromal cells. The release of mature neutrophils into the circulation coincides with the downregulation of CXCR4 expression, and concomitant increase in expression of CXCR2, a receptor for IL-8. However, senescent neutrophils increase CXCR4 expression again [17], which is thought to lead to their return to the BM where they are cleared by resident macrophages. In addition to its role in mediating cell retention in the BM, CXCR4 signaling has been proposed as a direct regulator of neutrophil lifespan. In mice, CXCR4 expression is increased in neutrophils after migration to the lungs and correlates with increased lifespan [29]. In patients with COPD, neutrophils are present in large numbers within the bronchoalveolar lavage fluid (BALF) [30] and express higher levels of CXCR4 compared to control subjects [31]. Similarly, neutrophils isolated from the sputum of CF patients showed increased surface expression of CXCR4 compared to blood neutrophils [32], and its ligand CXCL12 was detected in some CF sputum samples, suggesting a potential role of this pathway within the CF airway lumen.

In addition to the CXCR4/CXCL12 axis, new insights from the zebrafish model of neutrophil development show that signaling through the oxygen-dependent transcription factor hypoxia-inducible factor-1α (HIF-1α) can also significantly delay neutrophil apoptosis [33]. Since affected areas in CF lungs become highly hypoxic due to mucus impaction and fast oxygen consumption by activated neutrophils [34], it is tempting to speculate that HIF-1α signaling may be triggered in neutrophils present in this pathological microenvironment, affecting their lifespan. Consistent with this notion, significant HIF-1α signaling has been demonstrated in the βENaC mouse model of CF lung disease, inducing substantial pro-inflammatory signaling within the epithelium that results in neutrophilic inflammation [35].

Interestingly, it has been suggested that neutrophils in CF patients have an intrinsic increase in lifespan due to the mutation of the CFTR gene. Indeed, ex vivo experiments on blood neutrophils isolated from healthy controls and CF patients with the F508Del mutation showed delayed apoptosis in the latter [36, 37]. However, these data do not imply increased lifespan in vivo. Also, since ongoing treatments can significantly impact neutrophil behavior [38], it is likely that drugs administered to CF patients from whom neutrophils are collected can alter the lifespan of these cells ex vivo. Another interesting factor to consider when reflecting on potential influences exerted onto neutrophil lifespan is that of the resident microorganisms. Indeed, it has been demonstrated that neutrophil biogenesis and aging in mice is controlled, in part, by the gut microbiome [39, 40]. In patients with chronic infections, e.g., CF or COPD, it is likely that the lung microbiome could also play a role in shaping neutrophil lifespan [41], although this notion remains controversial [42, 43].

In the context of a normal immune response to an insult, increased neutrophil lifespan can be beneficial for the host, at least temporarily. However, if this response becomes dysregulated, it can constitute a double-edged sword [44]. To this day, many questions relative to the recruitment of neutrophils and their precise lifespan within the CF lung in vivo remain unanswered. A key difficulty resides in studying these mechanisms in vivo, and in untangling factors intrinsic to CF (compared to other diseases with similar neutrophilic inflammation, such as COPD), and those affected by exogenous drugs. Finally, since neutrophils, the airway epithelium, and microorganisms all contribute to CF lung disease, integrative approaches combining signals from all components of this pathological microenvironment are needed to yield better understanding of the mechanisms at play.

Overview of effector functions

In the course of inflammation, neutrophils recruited from blood cross into tissues and organize themselves in “swarms” to travel to the site of injury. Neutrophil migration responds to gradients of exogenous and autocrine/paracrine chemokines (e.g., IL-8), cytokines (e.g., tumor necrosis factor α), as well as bioactive lipids (e.g., leukotriene B4 (LTB4)) [45, 46]. Dynamic expression of specific receptors to these chemokines, cytokines, and bioactive lipids is critical to neutrophil migration. In addition, neutrophils express a plethora of pattern recognition receptors (PRRs) that allow them to sense and capture signals present in their surroundings in the form of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) [47]. PAMPs (e.g., lipopolysaccharide from gram-negative bacteria) and DAMPs (e.g., extracellular advanced glycation endproducts or adenosine triphosphate) are present in damaged tissues and play a major role in influencing the functional fate of incoming neutrophils, notably the mobilization of intracellular granules.

Neutrophil granules are designated based on their content and order of production during BM development. Primary or azurophilic granules are formed at the early stages of neutrophil lineage formation in the BM (myeloblast to promyelocyte) and contain the potent proteases neutrophil elastase (NE) and cathepsin G, the chlorinating enzyme myeloperoxidase (MPO), and defensins. Secondary or specific granules arise at the later metamyelocyte stage and are characterized by the presence of lactoferrin, collagenase, carcinoembryonic antigen cell adhesion molecule family members CD66a and CD66b, and the antiprotease cystatin C. Tertiary or gelatinase granules appear at the band cell stage, right before the final segmented stage of neutrophil BM development, and enclose lysozyme and matrix metalloproteinase 9 (MMP9). Secretory vesicles are present only in mature neutrophils and are thought to be produced by endocytosis of surface expressed proteins, enabling their rapid redeployment at the surface upon activation, as exemplified by the upregulation of PRR surface expression upon priming in blood [48, 49]. Mobilization of secretory vesicles followed by tertiary and secondary granules appears to be a default activation path for neutrophils. By contrast, primary granules generally fuse either with the phagosome or the nucleus [50], the latter being part of the recently discovered NETotic fate of neutrophils. During NETosis, DNA is decondensed, released along with histones, and complexed with cationic primary granule proteins (chiefly NE and MPO), thus forming extracellular traps endowed with antimicrobial activities [51].

Until recently, it was believed that, due to the high self-harming potential of primary granule enzymes, the content of primary granules was rarely if ever discharged actively in the extracellular environment during the normal course of an inflammatory response. Thus, the massive amounts of NE and MPO present in the pathological milieu of CF and COPD airway fluid were thought to stem from the passive release of primary granules following neutrophil necrosis. However, the discovery of viable neutrophils in the CF lung lumen capable of active primary granule exocytosis has overturned this belief [52]. In these cells, mobilization of primary granules to the plasma membrane is not a passive outcome, but rather a finely orchestrated mechanism leading to a fate distinct from phagocytosis and NETosis (Fig. 1). The molecular mechanisms behind the differential primary granule mobilization to the phagosome (phagocytosis), nucleus (NETosis), or plasma membrane (third, and presumably distinct, fate), and whether each of the three described fates is exclusive of the others, are but a few examples of the current mysteries surrounding neutrophil biology that will have to be addressed in future research.
https://static-content.springer.com/image/art%3A10.1186%2Fs40348-016-0066-2/MediaObjects/40348_2016_66_Fig1_HTML.gif
Fig. 1

Primary granule mobilization and functional fates of human neutrophils. Recent studies have revealed the existence of multiple functional fates of neutrophils, which lead to different interactions with incoming bacteria (in red). Fusion of primary granules (in blue) to the phagosome drives neutrophils toward the classical phagocytic fate (1), while their mobilization to the nucleus drives them toward the extrusion of DNA-based extracellular traps in a process called “NETosis” (2). By contrast, primary granule fusion with the plasma membrane instead leads to hyperexocytosis and potential reprogramming (3), a third fate that further emphasizes the functional plasticity of human neutrophils

Focus on neutrophil elastase

A major effector of neutrophils with a critical role in CF is neutrophil elastase (NE), a serine protease composed of 218 amino acids. First discovered in 1968 by Janoff and Scherer [53] in the granular fraction of neutrophils, it took 15 more years for the sequence of NE to become known [54]. Upon primary granule release, the majority of NE remains bound to the plasma membrane [55, 56], which enables it to have its catalytic region facing the extracellular environment while concealing its regulatory region, thus making inhibitors less effective. The important pathophysiological role played by NE is highlighted by the fact that NE-knockout mice are highly susceptible to sepsis induced by gram-negative bacteria [57]. In humans, cyclic neutropenia, a genetic disease caused by mutations in the NE-coding ela2 gene, is associated with recurrent troughs in neutrophil production and heightened susceptibility to infections, suggesting a dual developmental and functional role for NE [58, 59].

In CF, increased presence of active NE in the airway fluid of pediatric and adult patients has been correlated with impaired structural integrity, worsening lung function, and decreased body mass index over time [6063]. In a recent study, detectable NE activity in BALF of 3-month-old CF infants was the best predictor of future bronchiectasis development, with a likelihood seven times higher at 12 months and four times higher at the age of three than 3-month-old CF infants with no detectable NE in BALF activity [62]. Since BALF is highly diluted, due the way it is collected, it is possible that detection of free NE activity in CF infants happens only after constant NE release has overcome the secreted antiprotease shield present in the airways, thereby crossing a certain pathological threshold. Thus, more sensitive methods for extracellular NE detection are required in order to detect abnormal neutrophilic inflammation before it reaches a critical level and causes significant pathology.

Complementing early work by Owen and colleagues demonstrating NE activity in close vicinity to the plasma membrane of exocytosing neutrophils [55], additional work needs to be performed to determine the exact localization of NE in the extracellular environment within CF and COPD airways in vivo. Recently, Schulenburg et al. [64] designed a Förster resonance energy transfer probe specific for NE activity that could serve such a purpose. Potential applications of such probes have been extensively reviewed elsewhere [65]. Due to the wide range of proteins with NE cleavage sites that could potentially serve as NE substrates within pathological environments (see Table 1), it is hard to predict which of these proteins will be effectively proteolyzed in vivo. Among these proteins, one finds both immunological and non-immunological target proteins expressed by neutrophils, T cells, macrophages, and epithelial cells. Further adding to this complex picture, NE can be acquired by neighboring cells following its release by neutrophils [66]. This effectively extends the number of possible targets of NE-mediated cleavage to include intracellular proteins, which in turn affect signaling in neighboring cells (Table 2).
Table 1

Direct targets of NE-dependent regulation

Immunological targets

Activated by cleavage

Inhibited by cleavage

 Arginase-1 [106]

 CD2/CD4/CD8 [107]

 Chemerin [161]

 CD14 [162]

 IL-36 receptor antagonist [163]

 CD16 [164]

 IL-8 [84]

 CD43 [165]

 MMP-9 [67]

 CCL3 [166]

 PAR-1/PAR-2 [167, 168]

 Complement factors [169172]

 Pro-IL-1β [173]

 CXCL12 [174]

 Transient receptor potential vanilloid 4 [67]

 CXCR1 [82]

 Tumor growth factor α [175]

 IgA [70] and IgG [71, 72]

 

 IL-2 receptor [108]

 

 IL-6 [176, 177]

 

 IL-8 [86]

 

 PAR-3 [168]

 

 Progranulin [178, 179]

 

 TIMP-1/TIMP-2/TIMP-3 [180, 181]

Non-immunological targets

Activated by cleavage

Inhibited by cleavage

 α2β3 integrins [182]

 Cadherins [183]

 EGFR [184]

 Elastin [185]

 ENaC [186, 187]

 Ferritin [188]

 

 Fibrin stabilizing factor XIII [189]

 

 Surfactant protein A [190]

 

 Surfactant protein D [191]

 

 Vascular endothelial growth factor [192]

EGFR epidermal growth factor receptor, ENaC epithelial sodium channel, PAR protease-activated receptor, TIMP tissue inhibitor of metalloproteinase

Table 2

Indirect targets of NE-dependent regulation and cognate signaling pathways

Regulatory target

Modulation by NE

Signaling pathway

β-defensin 2 [193]

Activation

Unknown

Cathepsin B [194]

Activation

TLR4/IRAK

CFTR [97]

Inhibition

Calpain

P. aeruginosa flagellin [81]

Inhibition

Unknown

IL-12 p40 [195]

Activation

PAR-2/EGFR/TLR4

IL-8 [83, 192, 196, 197]

Activation

TLRs/MyD88/IRAK/TRAF-6

MHC I [198]

Activation

Unknown

MMP-2 [194]

Activation

TLR4/IRAK

MUC5AC [199, 200]

Activation

EGFR

EGFR epidermal growth factor receptor, ERK extracellular-regulated kinase, IRAK-1 IL-1 receptor associated kinase-1, MHC I major histocompatibility complex I, PAR-2 protease-activated receptor-2, TLR4 Toll-like receptor 4

A prototypical example highlighting the impact of unopposed NE activity in a pathological milieu is its ability to activate MMP9, another potent neutrophil protease. Upon concomitant release of primary and tertiary granules, NE can potentiate MMP9 through direct activatory cleavage and/or indirect degradative cleavage of its inhibitor tissue inhibitor of metalloprotease-1 (TIMP-1), leading to increased collagen degradation, tissue damage, and bronchiectasis in CF children [67, 68]. Likewise, surface phagocytic receptors CD14 and CD16 on neutrophils found in the lumen of CF patients’ lungs are inactivated by NE in autocrine and paracrine fashion [69]. Moreover, antibody-mediated bacterial killing is impaired not only on the receptor side but also on the opsonization potential of the antibody. As matter of fact, it has been shown that NE can cleave immunoglobulins A (IgA) [70] and G (IgG) [71, 72] near their hinge region. This leads to the formation of Fab and Fc fragments that are able to bind separately to the bacteria and receptors on target cells, thus losing the adaptor function of the antibody [73, 74]. In addition to NE, the CF opportunistic pathogen Pseudomonas aeruginosa also contributes its own elastase activity, which can also cleave IgG [75]. This dual inhibition exerted by NE on antibodies present in the CF airway lumen has implications for the design of vaccine strategies aiming to induce anti-bacterial responses in CF, suggesting that these may be severely limited by the high extracellular NE burden. Another example of effector function modulation by NE is the cleavage of the IL-8 receptor CXCR1, associated with impaired bacterial killing [76]. This may contribute to the infection by opportunistic bacteria such as Staphylococcus aureus and P. aeruginosa, which are also hallmarks of CF lung disease [77, 78]. Whether NE-mediated damage is a primary cause of these persistent infections or whether other elements in the CF lung environment also contribute to impaired clearance of these specific bacteria remains a matter of debate [79, 80].

Beyond the failed clearance of these bacteria, their continued adaptation to the CF environment, notably their switch to mucoid and biofilm resistance phenotypes, may also benefit from NE activity. Indeed, NE-mediated activity can repress flagellin transcription in P. aeruginosa, which facilitates biofilm formation [81]. Interestingly, NE-produced fragments of CXCR1 were identified as potential contributors to epithelial activation and release of IL-8 in a Toll-like receptor 2 (TLR2)-dependent manner [82], thus creating a pathological feedback loop of neutrophil recruitment, NE release, CXCR1 cleavage on epithelial cells, and further neutrophil recruitment. Additional contributions to this positive feedback loop come from the NE-mediated transcriptional upregulation of IL-8 via MyD88/IRAK/TRAF-6 [83] and direct NE-mediated processing of IL-8 in the extracellular milieu [84]. Indeed, IL-8 is produced as a 99-amino acid precursor protein which is proteolytically cleaved at its N-terminus before release [85]. Once in the extracellular milieu, IL-8 can be further processed by extracellular proteases, such as NE, leading to different bioactive forms that vary from 77 to 69 amino acids in length, with the 72-amino acid form being the most potent [84]. In vitro studies also suggest that IL-8 can be ultimately degraded in an NE-dependent manner over time [86] which could serve to balance out the induction of IL-8 production and its post-transcriptional activation by NE.

It is worth mentioning that although exocytosis of primary granule content can be considered a hallmark of CF lung disease, this process is not homogeneously expressed among all neutrophils found in the CF airway lumen. Indeed, Makam et al. [32] proposed a subset classification of airway neutrophils based on their surface phenotype, with neutrophils initially migrating into the lumen and expressing low CD63 (limited primary granule exocytosis) and high CD16 expression on their surface, followed by the acquisition of high surface CD63 expression (high primary granule exocytosis) and concomitant loss of surface CD16. This striking phenotypic and functional transition and its implications for CF pathogenesis are discussed in more details below.

Impact of CFTR on neutrophil function

In humans, the impact of endogenous CFTR in shaping neutrophil effector functions is unclear, due in part to limitations in research tools. First, animal models, such as CFTR knockout mice, ferrets, pigs, and rats, still have not allowed researchers in the field to adequately recapitulate the natural history of CF lung disease as seen in patients, and particularly the central role played by neutrophils. Second, the CFTR protein is generally expressed at low levels in cells, which, combined with the paucity of reliable anti-CFTR antibodies, has made it difficult to establish the presence of significant CFTR expression in human neutrophils and how it may impact their function [8789].

To date, several lines of evidence support the notion that neutrophil effector functions are not intrinsically controlled by CFTR mutations. To begin with, the fact that CFTR knockout animal models do not recapitulate neutrophilic lung inflammation as seen in CF patients itself suggests that neutrophil dysfunction in CF patients is due to one or several coinciding mechanism(s) unique to humans, besides CFTR deficiency [90]. Additional support for this idea comes from a xenograft model in which human fetal tracheal tissues were implanted in severe combined immunodeficient mice [91]. In this model, mouse neutrophils (with normal CFTR expression) were recruited to CF but not non-CF xenogratfs, emphasizing the role of the CF airway microenvironment in triggering neutrophil dysfunction. Consistently, a recent study in primary airway epithelial cultures from CF and non-CF infants showed the existence of a pro-inflammatory imbalance at steady state and upon stimulation with a viral insult in the former compared to the latter [23]. Furthermore, restoring CFTR expression in the airway epithelium of CF mice is sufficient to restore normal bacterial clearance therein, which suggests a minimal role for CFTR expression in non-epithelial cells, at least in this model [92]. Intriguingly, selective knockout of CFTR in myeloid cells in another mouse strain led to a basal inflammatory dysfunction that was further accentuated upon infection [93], suggesting that in mice, the impact of CFTR on myeloid cells (including but not limited to neutrophils) may be dependent upon the strain and conditions tested.

From a microbiological perspective, the predominance of a handful of bacterial species in CF lungs in vivo suggests that neutrophil-mediated clearance may not be completely abolished in this setting, but rather that distinct evolutionary pressures are at play that are unlikely to be solely driven by CFTR-dependent dysregulation of neutrophil phagocytosis or degranulation. Indeed, a recent study showed that the CF lung pathogen P. aeruginosa is resistant to neutrophil-mediated extracellular killing, a process that is CFTR-independent [94]. Furthermore, if neutrophils in CF patients were intrinsically defective due to endogenous CFTR dysfunction, one would expect evidence of chronic infection and inflammation in organs other than the lungs, which is not the case.

It is also noteworthy that in COPD and non-CF bronchiectasis patients devoid of a hereditary CFTR defect, massive neutrophil transmigration also occurs in the lungs, with subsequent release of primary granules and impaired phagocytosis reminiscent of the picture seen in CF patients [95, 96]. This suggests that a primary defect in CFTR expression is not the root cause of neutrophilic inflammation in these disease contexts. It remains possible, however, that CFTR expression may be intrinsically normal in these patients, only to be downregulated post-translationally due to high extracellular activity of NE, thus affecting neutrophil fate [97]. In CF patients, chronic disease may lead to similar adaptive changes in blood neutrophils. This could account, for example, for the observed dysfunction of Rab27a in blood neutrophils from adult CF patients, a key protein involved in tertiary and secondary granule exocytosis, coupled with the finding that significant improvement in Rab27a function in these neutrophils can be brought upon by ex vivo treatment with the CFTR potentiator ivacaftor [98]. Proving the existence of an intrinsic defect in neutrophils in CF patients would ultimately require well-controlled data in infants, prior to the advent of chronic disease, a feat that has not been achieved so far. These and other novel approaches and experimental designs will be necessary to further elucidate the etiology of the abnormal neutrophil effector functions that are manifest in CF lungs.

Immunomodulatory role of neutrophils

Since the early 1960s, significant heterogeneity among circulating and tissue neutrophils has been recognized, and this notion has gained further traction recently as evidence of divergent immunomodulatory functions by neutrophil subsets are emerging in different pathological contexts [99]. One critical example lies in tumor microenvironments, where neutrophils can display a strong immunosuppressive phenotype, promoting tumor survival [100, 101]. As immunomodulatory cells, neutrophils modulate not only their own kin but also a variety of other immune and structural cells. To do so, neutrophils use a variety of chemokines and cytokines that regulate other cells acutely and have the potential to induce chronic signaling loops that shape the long-term immune response [102, 103].

In CF, the lumen of the lung is brimming with neutrophils, while it is conspicuously devoid of T cells. The enzyme arginase-1 can be released by neutrophils, as well as M2-polarized macrophages and dendritic cells, leading to depletion of extracellular arginine, which in turn can inhibit T cell activity. Arginase-dependent T cell inhibition is common in tumor microenvironments [104] and upon infection with certain viruses [105]. In CF lungs, arginase-1 is released by neutrophils, making the airway lumen a highly inhibitory milieu for T cells [106]. In addition to the strong inhibitory role played by neutrophil-derived arginase-1, neutrophil-derived elastase can also cleave multiple critical T cell coreceptors, therefore blocking T cell activation (see references [107] and [108], and Table 1). Furthermore, programmed death ligand 1 (PD-L1), a known inhibitor of T cell function in a variety of pathologies and a major target for immunotherapy [109], was also found to be expressed in human airway neutrophils at higher levels than on their blood counterparts (in both CF and healthy subjects), but with a characteristic bimodal expression in CF. In addition, soluble PD-L1 was also detected in CF, but not healthy, airway fluid [106]. The precise role of cell-associated and soluble PD-L1 on T cell modulation in CF remains to be fully explored.

Interestingly, the impact of CF airway neutrophils on T cell function may not be solely inhibitory, since these cells were shown to increase expression of the T-activatory surface receptors major histocompatibility complex II, co-activator CD80, and prostaglandin D2 receptor CD294, further underlining their plasticity [69]. Expression of major histocompatibility complex II and CD80 is conventionally thought to be the prerogative of professional antigen-presenting cells, such as dendritic cells and macrophages, while CD294 is a marker for Th2-polarized immune cells in the context of allergy and hypersensitivity reactions [110]. The exact role of these T-activatory proteins on the surface of CF airway neutrophils has yet to be determined, although one can speculate a possible role in skewing T cell responses that may occur in spite of arginase-1 and NE-dependent inhibition. Indeed, it has been observed that CD4+ T cells in CF mouse models [111] and human CF airway samples and tissues [112115] are skewed toward pro-inflammatory Th2/Th17 responses, while inhibitory T-regulatory function is inhibited.

Positive regulation of T cells by neutrophils was also suggested in early-stage human non-small cell lung cancer [116], in which tumor-associated neutrophils expressing typical antigen-presenting cell markers were able to induce T cell activation ex vivo. A recent study has also shown the importance of neutrophils in promoting a protective Th17 T cell response upon vaccination against tuberculosis [117]. Since Th17 cells and their product IL-17 create a positive feedback loop for neutrophil recruitment by tissues [118], neutrophil/T cell interplay may be critical to pathogenesis in CF and other relevant diseases. Rheumatoid arthritis (RA) is another example of a chronic disease in which neutrophils recruited from blood to the synovium dominate signaling loops to induce a skewed immune response [119].

Metabolic licensing of neutrophils

The CF lung lumen is a very peculiar microenvironment in terms of oxygen, and metabolite content. The normal lung lumen is oxygen-rich due to constant breathing activity. However, in diseased areas within the CF lung lumen, neutrophil clusters, bacterial and/or fungal colonies, and inspissated extracellular scaffolds of mucus, DNA, and actin can lead to profound oxygen depletion. Local hypoxia can in turn promote inflammation through the release of DAMPs from host epithelial cells [35, 120, 121]. Furthermore, the CF lung environment has a distinct metabolite composition, presumably as a consequence of both CFTR dysfunction and of the chronic presence of neutrophils and microbiota in the lumen. First, it has been suggested that CFTR, although functioning primarily as a chloride and bicarbonate channel [122], can also enable transmembrane flux of the redox intermediates glutathione (GSH) and thiocyanate [123125]. CFTR is also indirectly involved in the control of neutral amino acid transport across the epithelium [126]. In addition, the CF lung lumen was shown to contain abnormal levels of nucleotides [127], glucose, and peptides [128].

The composition of the CF airway milieu drives adaptations in neutrophils, and in turn, these adaptations influence this pathological microenvironment. A telling example is that of the redox imbalance that constitutes a hallmark of CF. Local and systemic accumulation of oxidants are believed to impact CF blood neutrophils, which display lower intracellular GSH levels [69]. Meanwhile, reactive oxygen species produced by neutrophils including hypochlorous acid (bleach), a byproduct of the enzyme MPO exocytosed from primary granules at the same time as NE, can quickly and profoundly oxidize the lung microenvironment [129]. Finally, neutrophils can contribute to extracellular GSH catabolism, by expressing at their surface the GSH-metabolizing enzyme gamma-glutamyltransferase [130]. Another example is that of arginine, which neutrophils can deplete from the CF airway lumen by releasing arginase-1 [131] from their granules [132]. Consequently, low availability of arginine results in decreased nitric oxide production [133] and high levels of arginine degradation products ornithine and polyamines [134].

From an intracellular signaling standpoint, comparative studies conducted in blood and airway neutrophils collected from CF patients in vivo showed that these do not differ with regard to their levels of active, phosphorylated forms of the critical intermediate kinases Akt, c-Jun-related kinase, p38 mitogen-activated protein kinase, and p44/42 extracellular-regulated kinase or of the pro-inflammatory transcription factors, nuclear factor κB p65, and signal transducer and activator of transcription 5 [69]. However, CF airway neutrophils had increased levels of phosphorylated forms of effector proteins in the mammalian target of rapamycin pathway, a major anabolic switch. These included phosphorylated S6 ribosomal protein [69], eukaryotic initiation factor 4E, and 4E-binding protein 1 [32]. Additionally, levels of the phosphorylated cyclic AMP-response element binding protein, as well as its upstream sensors, CD114 and receptor for advanced glycation endproducts, and downstream targets, CD39 and CXCR4, which function together as another anabolic switch in cells, were found to be increased in CF airway neutrophils [32]. In aggregate, these results suggest that CF airway neutrophils are licensed by the microenvironment to become anabolic, i.e., to use resources at their disposal to survive and expand their functions.

Insights gained from the analysis of intracellular phosphorylation cascades in CF airway neutrophils were confirmed by analysis of nutrient transporter expression. Compared to their blood counterparts, CF airway neutrophils as a whole displayed high expression of the inorganic phosphate transporter PiT1 (necessary for ATP synthesis) and of the glucose transporter Glut1, coinciding with increased glucose uptake [135]. Subset analysis of CF airway neutrophils showed that the degranulation of primary granules typical of the A2 subset was associated with higher expression of Glut1 and PiT1, and of the other inorganic phosphate transporter PiT2. Expression of CD98, a shared subunit of multiple amino acid transporters, did not differ in CF airway compared to blood neutrophils [32], but that of ASCT2, a neutral amino acid transporter, was highly upregulated in the A2 subset [135]. It is likely that this metabolic surge leads to de novo transcription and protein production in CF airway neutrophils, since neutrophils recruited to other pathological environments, e.g., the synovium of RA patients, have shown an ability to increase mRNA output [49, 136, 137].

The combined massive and sustained recruitment of neutrophils from blood into CF lungs (presumably leading to an increased neutrophil production in the BM), and increased metabolic activity of these neutrophils once they have reached the CF airway lumen are expected to impact lung tissue function and systemic metabolism in patients. Indeed, the severity of CF lung inflammation has been correlated not only to a decreased lung function [138] but also to decreased body mass index [61], decreased heart function [139], and cardiovascular complications [140]. Generally, the establishment of a complex microenvironment involving not only the chronic and massive presence of neutrophils but also large populations of bacteria (and/or fungi) in the airway lumen may increase the metabolic share taken by the lung, at the expense of other organs [141].

The relationship between inflammation, high cellular turnover, and increased systemic energy expenditure is not confined to CF, but rather is a common feature of an array of chronic human diseases. For example, high body mass index at late cancer stages predicts a higher survival rate [142]. Understanding the mechanism underlying the anabolic switch in CF airway neutrophils and the interplay between the different actors within the CF lung microenvironment could help identify treatments impacting not only lung disease but also the overall metabolic balance in patients.

The CF airway microenvironment

The existence of discrete microenvironments within the human body is not a new concept. This concept is exemplified by the gut mucosa, featuring fine-tuned interplay between the resident flora in the lumen and the immune cells in the lamina propria, with the epithelium as an interface. While the gut mucosa represents a normal microenvironment, it can also become imbalanced in the context of inflammatory bowel disease. Other pathological conditions can lead to the formation of microenvironments in organs that do not normally harbor a significant, stable population of inflammatory cells and/or associated microbiota. CF, RA, and several forms of cancer serve as examples of such pathological microenvironments featuring a dominant neutrophilic component.

A key element in the formation of pathological microenvironments is the establishment of tolerance and cooperation between the different players, enabling an acute process to become chronicized. For instance, inflammatory bowel disease is characterized by a massive neutrophil infiltration in the gut [143, 144] and as the disease progresses, neutrophils orchestrate with the gut epithelium the advent of a chronic state. Consequently, adaptive responses are dampened [145], and neutrophils and bacteria coexist in concentric luminal structures termed “casts” [146]. A similar scenario unfolds in CF, where neutrophils interact with the airway epithelium and opportunistic bacteria such as P. aeruginosa and S. aureus to establish multi-decade colonies, featuring minimal involvement of adaptive immune cells, and structures in the lumen where bacteria and neutrophils coexist [147].

Recent studies suggest that the formation of pathological microenvironments featuring substantial relocation of hematopoietic cells within a peripheral organ can impact other distal organs besides the BM, where hematopoiesis takes place. For example, Masri et al. [148] have shown that establishment of a lung tumor mass can lead to re-tuning of the liver circadian clock and reprogramming of its nutrient output in order to support the metabolic requirements of the remote lung tumor. Whether the establishment of a pathological microenvironment in the CF lung does not only involve complex local coordination but also impact other organs in the body (notably the liver and gut, in order to respond to its metabolic demands) remains to be established. Taken together, evidence from in vivo and in vitro studies suggest that, at a minimum, the airway epithelium, recruited neutrophils, and bacteria present in the CF microenvironment coevolve over time to enable a somewhat peaceful, albeit tissue-damaging, coexistence, as illustrated in Fig. 2.
https://static-content.springer.com/image/art%3A10.1186%2Fs40348-016-0066-2/MediaObjects/40348_2016_66_Fig2_HTML.gif
Fig. 2

Development and evolution of a pathological microenvironment in CF airways. From birth to adulthood, CF patients undergo stepwise changes to their airway microenvironment. In the first phase (left), neutrophil start to accumulate in the lumen in response to cues from the underlying epithelium, prior to the advent of chronic infection. The second phase (middle) features the stable coexistence of an even more substantial population of luminal neutrophils with planktonic bacteria (in red, drawn with flagellum to exemplify P. aeruginosa, the gram-negative pathogen most commonly found in CF patients). In the third phase (right), bacteria switch to a resistant and generally avirulent and auxotrophic mode of existence, encased in an extracellular molecular scaffold (mucoid or biofilm forms, in yellow), with a very large population of neutrophils organized as a cast around them. Shown under the epithelium are the critical environmental conditions that change during the formation of this pathological microenvironment, including the degree of airway obstruction (increasing), and luminal levels of oxygen (decreasing as neutrophil activate their reactive oxygen species burst) and lactic acid (increasing with neutrophil glycolytic activity), pH (decreasing as lactic acid accumulates), as well the burden of free NE and DNA (both correlated positively with neutrophil presence)

Treatment opportunities

The development of drugs aimed to treat CF has mainly focused on fluidifying secretions, regulating microbial burden and, more recently, rescuing mutant CFTR function. The latter approach has paid substantial dividends with the drug ivacaftor for CFTR gating mutants such as G551D. However, the downside of this approach is that it is mutation-specific and benefits only a small percentage of CF patients [149]. So far, only little attention has been paid to the regulation of neutrophil function, since the long-held view has been that these cells die quickly upon migration to CF lungs. Data discussed in this review clearly contradict this view and open new avenues for neutrophil-focused therapies in CF.

Conventional anti-inflammatory drugs, including ibuprofen and prednisone, have shown beneficial, albeit marginal, effects by slowing down CF disease progression [150, 151]. However, prednisone treatment of CF patients is not common due to important side effects on growth [152]. More recent efforts focused on drugs designed to inhibit neutrophil recruitment to the CF lung, such as BIIL 284, a LTB4 receptor antagonist [153], and SB 656933, a CXCR2 antagonist [154]. Both drugs led to an increase in inflammatory signaling (increased frequency of exacerbations for the former, and increased circulating inflammatory mediators for the latter), suggesting that inhibiting neutrophil recruitment to the CF lung may prove detrimental for patients [155]. In addition to inhibiting neutrophil recruitment into the lung lumen, BIIL 284 was also found to promote apoptosis of neutrophils that had transmigrated [156]. Arguably, focus should now be put on the development of drugs directed toward regulating neutrophil function or aiming to orchestrate their chemotaxis to the lung to attain normal homeostatic levels, rather than blocking their recruitment, which could lead to detrimental, sub-normal levels of these cells within the lung lumen.

Since NE activity is elevated in CF patients and correlates with disease progression, development of NE inhibitors has been of prime interest [157, 158]. Unfortunately, due to the high amount of NE present in CF airways, its broad range of substrates, and its compartmentalization as both a free-floating, mucus-associated, and membrane-bound enzyme [55], the design of inhibitors and modes of administration have to be significantly improved to attain therapeutic efficacy [159]. In a recently introduced approach, Forde et al. [160] leveraged NE activity in diseased airways to process a synthetic pro-drug, giving rise to a fully active anti-infectious small peptide. A similar approach could be applied to design NE-activated immunomodulatory drugs. Examples of relevant immunomodulatory drugs includes agents able to (i) target the organizing stage of neutrophil swarming preceding their transepithelial migration, which may reduce, as opposed to fully abrogate their recruitment to the lung; (ii) manipulate the metabolism and/or functional fate of neutrophils, to promote phagocytosis while reducing NETosis and degranulation/reprogramming; and (iii) regulate the lifespan of airway neutrophils or interfere with other factors enabling the establishment of a pathological, neutrophil-driven microenvironment in CF lungs.

Conclusions

In the last decade, monumental progress has been made to understand the processes characterizing the peculiar situation of CF lung disease. Despite extensive work, there is much more to be explored regarding neutrophil functions and plasticity, and their ability to occupy a central place in the development of a pathological microenvironment in CF lungs (Fig. 3).
https://static-content.springer.com/image/art%3A10.1186%2Fs40348-016-0066-2/MediaObjects/40348_2016_66_Fig3_HTML.gif
Fig. 3

Neutrophils as protagonists among contributors to CF airway disease. Neutrophils (center) establish metabolic and signaling ties with lung epithelial cells (bottom right) and resident planktonic and mucoid/biofilm bacteria (bottom left), while exerting primarily inhibitory control over other immune cells, including T cells and macrophages (top). The result of these complex relationships is the formation of a relatively stable pathological microenvironment within CF airways

Neutrophils currently enjoy renewed interest from basic and clinical researchers, as emerging evidence supports the idea that mechanisms of metabolic and functional plasticity described here are not confined to CF. Therefore, a better understanding of molecular mechanisms underlying neutrophil plasticity and neutrophil-epithelium-microbial partnership should help identify novel targets for treatments aiming to normalize pathological microenvironment development in CF, and similar neutrophil-driven diseases such as COPD, RA, and certain forms of cancer. Expanding our knowledge in terms of crosstalk between metabolic switching, interconnecting pathways and effector functions in neutrophils will be of high value for innumerable reasons. To close this review, we invite readers to consult Fig. 4, which lists several of the open questions pertaining to neutrophil plasticity and function that will need to be addressed in the near future.
https://static-content.springer.com/image/art%3A10.1186%2Fs40348-016-0066-2/MediaObjects/40348_2016_66_Fig4_HTML.gif
Fig. 4

Open questions related to human neutrophil fate and their role in the formation of pathological microenvironments

Abbreviations

BALF: 

Bronchoalveolar lavage fluid

BM: 

Bone marrow

CF: 

Cystic fibrosis

CFTR: 

Cystic fibrosis transmembrane conductance regulator

COPD: 

Chronic obstructive pulmonary disease

DAMPs: 

Damage-associated molecular patterns

GSH: 

Glutathione

HIF1α: 

Hypoxia-inducible factor 1α

IL-8: 

Interleukin-8

MMP9: 

Matrix metalloproteinase 9

MPO: 

Myeloperoxidase

NE: 

Neutrophil elastase

PAMPs: 

Pathogen-associated molecular patterns

PAR: 

Protease-activated receptor

PD-L1: 

Programmed death ligand 1

RA: 

Rheumatoid arthritis

TIMP: 

Tissue inhibitor of metalloproteinase

TLR: 

Toll-like receptor

Declarations

Acknowledgements

We would like to acknowledge B. Ford for early edits to the manuscript and research groups that have contributed to this field of research. We apologize for omitting select studies from the bibliography due to limitations inherent to this review.

Funding

NIH/NHLBI R01HL126603 and CF Foundation TIROUV15A0 were given to RT.

Authors’ contributions

CM and RT defined the plan for the manuscript and content of tables and figures; CM drafted the manuscript, tables, and figures; RT corrected and undertook the final editing. Both authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors’ Affiliations

(1)
Department of Pediatrics, Emory University School of Medicine
(2)
Center for CF and Airways Disease Research, Children’s Healthcare of Atlanta
(3)
Emory + Children’s Center

References

  1. Linsdell P, Tabcharani JA, Rommens JM, Hou YX, Chang XB, Tsui LC, Riordan JR, Hanrahan JW (1997) Permeability of wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels to polyatomic anions. J Gen Physiol 110:355–364View ArticlePubMedPubMed CentralGoogle Scholar
  2. Gao L, Kim KJ, Yankaskas JR, Forman HJ (1999) Abnormal glutathione transport in cystic fibrosis airway epithelia. Am J Physiol 277:L113–L118PubMedGoogle Scholar
  3. Elborn JS (2016) Cystic fibrosis. Lancet doi: 10.1016/S0140-6736(16)00576-6
  4. Egan ME (2016) Genetics of cystic fibrosis: clinical implications. Clin Chest Med 37:9–16View ArticlePubMedGoogle Scholar
  5. Schindler T, Michel S, Wilson AW (2015) Nutrition management of cystic fibrosis in the 21st century. Nutr Clin Pract 30:488–500View ArticlePubMedGoogle Scholar
  6. Stoltz DA, Meyerholz DK, Welsh MJ (2015) Origins of cystic fibrosis lung disease. N Engl J Med 372:1574–1575View ArticlePubMedGoogle Scholar
  7. Hartl D, Gaggar A, Bruscia E, Hector A, Marcos V, Jung A, Greene C, McElvaney G, Mall M, Doring G (2012) Innate immunity in cystic fibrosis lung disease. J Cyst Fibros 11:363–382View ArticlePubMedGoogle Scholar
  8. Sly PD, Wainwright CE (2016) Diagnosis and early life risk factors for bronchiectasis in cystic fibrosis: a review. Expert Rev Respir Med 10:1003–1010View ArticlePubMedGoogle Scholar
  9. Laval J, Ralhan A, Hartl D (2016) Neutrophils in cystic fibrosis. Biol Chem 397:485–496View ArticlePubMedGoogle Scholar
  10. Downey DG, Bell SC, Elborn JS (2009) Neutrophils in cystic fibrosis. Thorax 64:81–88View ArticlePubMedGoogle Scholar
  11. Cohen TS, Prince A (2012) Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med 18:509–519View ArticlePubMedPubMed CentralGoogle Scholar
  12. Bonfield TL (2015) Macrophage dysfunction in cystic fibrosis: a therapeutic target to enhance self-immunity. Am J Respir Crit Care Med 192:1406–1407View ArticlePubMedGoogle Scholar
  13. Siegmann N, Worbs D, Effinger F, Bormann T, Gebhardt M, Ulrich M, Wermeling F, Muller-Hermelink E, Biedermann T, Tighe M, Edwards MJ, Caldwell C, Leadbetter E, Karlsson MC, Becker KA, Gulbins E, Doring G (2014) Invariant natural killer T (iNKT) cells prevent autoimmunity, but induce pulmonary inflammation in cystic fibrosis. Cell Physiol Biochem 34:56–70View ArticlePubMedGoogle Scholar
  14. Bruscia EM, Bonfield TL (2016) Innate and adaptive immunity in cystic fibrosis. Clin Chest Med 37:17–29View ArticlePubMedGoogle Scholar
  15. Silvestre-Roig C, Hidalgo A, Soehnlein O (2016) Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 127:2173–2181View ArticlePubMedGoogle Scholar
  16. Tak T, Tesselaar K, Pillay J, Borghans JA, Koenderman L (2013) What’s your age again? Determination of human neutrophil half-lives revisited. J Leukoc Biol 94:595–601View ArticlePubMedGoogle Scholar
  17. Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, Chilvers ER (2010) Neutrophil kinetics in health and disease. Trends Immunol 31:318–324View ArticlePubMedPubMed CentralGoogle Scholar
  18. Dibbert B, Weber M, Nikolaizik WH, Vogt P, Schoni MH, Blaser K, Simon HU (1999) Cytokine-mediated bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation. Proc Natl Acad Sci U S A 96:13330–13335View ArticlePubMedPubMed CentralGoogle Scholar
  19. Kennedy AD, DeLeo FR (2009) Neutrophil apoptosis and the resolution of infection. Immunol Res 43:25–61View ArticlePubMedGoogle Scholar
  20. Zurek OW, Pallister KB, Voyich JM (2015) Staphylococcus aureus inhibits neutrophil-derived IL-8 to promote cell death. J Infect Dis 212:934–938View ArticlePubMedPubMed CentralGoogle Scholar
  21. Greenlee-Wacker MC, Rigby KM, Kobayashi SD, Porter AR, DeLeo FR, Nauseef WM (2014) Phagocytosis of Staphylococcus aureus by human neutrophils prevents macrophage efferocytosis and induces programmed necrosis. J Immunol 192:4709–4717View ArticlePubMedPubMed CentralGoogle Scholar
  22. Manago A, Becker KA, Carpinteiro A, Wilker B, Soddemann M, Seitz AP, Edwards MJ, Grassme H, Szabo I, Gulbins E (2015) Pseudomonas aeruginosa pyocyanin induces neutrophil death via mitochondrial reactive oxygen species and mitochondrial acid sphingomyelinase. Antioxid Redox Signal 22:1097–1110View ArticlePubMedPubMed CentralGoogle Scholar
  23. Sutanto EN, Kicic A, Foo CJ, Stevens PT, Mullane D, Knight DA, Stick SM, Australian Respiratory Early Surveillance Team for Cystic F (2011) Innate inflammatory responses of pediatric cystic fibrosis airway epithelial cells: Effects of nonviral and viral stimulation. Am J Respir Cell Mol Biol 44:761–767View ArticlePubMedGoogle Scholar
  24. Baggiolini M, Loetscher P, Moser B (1995) Interleukin-8 and the chemokine family. Int J Immunopharmacol 17:103–108View ArticlePubMedGoogle Scholar
  25. Kettritz R, Gaido ML, Haller H, Luft FC, Jennette CJ, Falk RJ (1998) Interleukin-8 delays spontaneous and tumor necrosis factor-alpha-mediated apoptosis of human neutrophils. Kidney Int 53:84–91View ArticlePubMedGoogle Scholar
  26. Adrover JM, Nicolas-Avila JA, Hidalgo A (2016) Aging: a temporal dimension for neutrophils. Trends Immunol 37:334–345View ArticlePubMedGoogle Scholar
  27. Casanova-Acebes M, Pitaval C, Weiss LA, Nombela-Arrieta C, Chevre R, A-González N, Kunisaki Y, Zhang D, van Rooijen N, Silberstein LE, Weber C, Nagasawa T, Frenette PS, Castrillo A, Hidalgo A (2013) Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153:1025–1035View ArticlePubMedPubMed CentralGoogle Scholar
  28. Ella K, Csepanyi-Komi R, Kaldi K (2016) Circadian regulation of human peripheral neutrophils. Brain Behav Immun 57:209–221View ArticlePubMedGoogle Scholar
  29. Yamada M, Kubo H, Kobayashi S, Ishizawa K, He M, Suzuki T, Fujino N, Kunishima H, Hatta M, Nishimaki K, Aoyagi T, Tokuda K, Kitagawa M, Yano H, Tamamura H, Fujii N, Kaku M (2011) The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury. Cell Mol Immunol 8:305–314View ArticlePubMedPubMed CentralGoogle Scholar
  30. Williams TJ, Jose PJ (2001) Neutrophils in chronic obstructive pulmonary disease. Novartis Found Symp 234:136–141View ArticlePubMedGoogle Scholar
  31. Hartl D, Krauss-Etschmann S, Koller B, Hordijk PL, Kuijpers TW, Hoffmann F, Hector A, Eber E, Marcos V, Bittmann I, Eickelberg O, Griese M, Roos D (2008) Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. J Immunol 181:8053–8067View ArticlePubMedGoogle Scholar
  32. Makam M, Diaz D, Laval J, Gernez Y, Conrad CK, Dunn CE, Davies ZA, Moss RB, Herzenberg LA, Herzenberg LA, Tirouvanziam R (2009) Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs. Proc Natl Acad Sci U S A 106:5779–5783View ArticlePubMedPubMed CentralGoogle Scholar
  33. Elks PM, van Eeden FJ, Dixon G, Wang X, Reyes-Aldasoro CC, Ingham PW, Whyte MK, Walmsley SR, Renshaw SA (2011) Activation of hypoxia-inducible factor-1alpha (HIF-1alpha) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood 118:712–722View ArticlePubMedGoogle Scholar
  34. Worlitzsch D, Tarran R, Ulrich M, Schwab U, Cekici A, Meyer KC, Birrer P, Bellon G, Berger J, Weiss T, Botzenhart K, Yankaskas JR, Randell S, Boucher RC, Doring G (2002) Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 109:317–325View ArticlePubMedPubMed CentralGoogle Scholar
  35. Fritzsching B, Zhou-Suckow Z, Trojanek JB, Schubert SC, Schatterny J, Hirtz S, Agrawal R, Muley T, Kahn N, Sticht C, Gunkel N, Welte T, Randell SH, Langer F, Schnabel P, Herth FJ, Mall MA (2015) Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis lung disease. Am J Respir Crit Care Med 191:902–913View ArticlePubMedPubMed CentralGoogle Scholar
  36. McKeon DJ, Condliffe AM, Cowburn AS, Cadwallader KC, Farahi N, Bilton D, Chilvers ER (2008) Prolonged survival of neutrophils from patients with Delta F508 cftr mutations. Thorax 63:660–661View ArticlePubMedGoogle Scholar
  37. Moriceau S, Lenoir G, Witko-Sarsat V (2010) In cystic fibrosis homozygotes and heterozygotes, neutrophil apoptosis is delayed and modulated by diamide or roscovitine: evidence for an innate neutrophil disturbance. J Innate Immun 2:260–266View ArticlePubMedGoogle Scholar
  38. Bratcher PE, Rowe SM, Reeves G, Roberts T, Szul T, Harris WT, Tirouvanziam R, Gaggar A (2016) Alterations in blood leukocytes of G551D-bearing cystic fibrosis patients undergoing treatment with ivacaftor. J Cyst Fibros 15:67–73View ArticlePubMedGoogle Scholar
  39. Mei J, Liu Y, Dai N, Hoffmann C, Hudock KM, Zhang P, Guttentag SH, Kolls JK, Oliver PM, Bushman FD, Worthen GS (2012) CXR2 and CXCL5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J Clin Invest 122:974–986View ArticlePubMedPubMed CentralGoogle Scholar
  40. Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, Burk RD, Kunisaki Y, Jang JE, Scheiermann C, Merad M, Frenette PS (2015) Neutrophil ageing is regulated by the microbiome. Nature 525:528–532View ArticlePubMedPubMed CentralGoogle Scholar
  41. Madan JC (2016) Neonatal gastrointestinal and respiratory microbiome in cystic fibrosis: potential interactions and implications for systemic health. Clin Ther 38:740–746View ArticlePubMedGoogle Scholar
  42. O’Dwyer DN, Dickson RP, Moore BB (2016) The lung microbiome, immunity, and the pathogenesis of chronic lung disease. J Immunol 196:4839–4847View ArticlePubMedGoogle Scholar
  43. Huang YJ, LiPuma JJ (2016) The microbiome in cystic fibrosis. Clin Chest Med 37:59–67View ArticlePubMedGoogle Scholar
  44. McCracken JM, Allen LA (2014) Regulation of human neutrophil apoptosis and lifespan in health and disease. J Cell Death 7:15–23PubMedPubMed CentralGoogle Scholar
  45. Majumdar R, Tavakoli Tameh A, Parent CA (2016) Exosomes mediate LTB4 release during neutrophil chemotaxis. PLoS Biol 14:e1002336View ArticlePubMedPubMed CentralGoogle Scholar
  46. Lammermann T, Afonso PV, Angermann BR, Wang JM, Kastenmuller W, Parent CA, Germain RN (2013) Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498:371–375View ArticlePubMedGoogle Scholar
  47. Thomas CJ, Schroder K (2013) Pattern recognition receptor function in neutrophils. Trends Immunol 34:317–328View ArticlePubMedGoogle Scholar
  48. Borregaard N, Sorensen OE, Theilgaard-Monch K (2007) Neutrophil granules: a library of innate immunity proteins. Trends Immunol 28:340–345View ArticlePubMedGoogle Scholar
  49. Theilgaard-Monch K, Porse BT, Borregaard N (2006) Systems biology of neutrophil differentiation and immune response. Curr Opin Immunol 18:54–60View ArticlePubMedGoogle Scholar
  50. Mollinedo F, Calafat J, Janssen H, Martin-Martin B, Canchado J, Nabokina SM, Gajate C (2006) Combinatorial SNARE complexes modulate the secretion of cytoplasmic granules in human neutrophils. J Immunol 177:2831–2841View ArticlePubMedGoogle Scholar
  51. Brinkmann V, Zychlinsky A (2012) Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol 198:773–783View ArticlePubMedPubMed CentralGoogle Scholar
  52. Tirouvanziam R, Khazaal I, Peault B (2002) Primary inflammation in human cystic fibrosis small airways. Am J Physiol Lung Cell Mol Physiol 283:L445–L451View ArticlePubMedGoogle Scholar
  53. Janoff A, Scherer J (1968) Mediators of inflammation in leukocyte lysosomes: elastinolytic activity in granules of human polymorphonuclear leukocytes. J Exp Med 128:1137–1155View ArticlePubMedPubMed CentralGoogle Scholar
  54. Sinha S, Watorek W, Karr S, Giles J, Bode W, Travis J (1987) Primary structure of human neutrophil elastase. Proc Natl Acad Sci U S A 84:2228–2232View ArticlePubMedPubMed CentralGoogle Scholar
  55. Owen CA, Campbell MA, Sannes PL, Boukedes SS, Campbell EJ (1995) Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases. J Cell Biol 131:775–789View ArticlePubMedGoogle Scholar
  56. Campbell EJ, Campbell MA, Owen CA (2000) Bioactive proteinase 3 on the cell surface of human neutrophils: quantification, catalytic activity, and susceptibility to inhibition. J Immunol 165:3366–3374View ArticlePubMedGoogle Scholar
  57. Belaaouaj A, McCarthy R, Baumann M, Gao Z, Ley TJ, Abraham SN, Shapiro SD (1998) Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat Med 4:615–618View ArticlePubMedGoogle Scholar
  58. Pham CT (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6:541–550View ArticlePubMedGoogle Scholar
  59. Dale DC, Bolyard AA, Aprikyan A (2002) Cyclic neutropenia. Semin Hematol 39:89–94View ArticlePubMedGoogle Scholar
  60. McMorran BJ, Patat SA, Carlin JB, Grimwood K, Jones A, Armstrong DS, Galati JC, Cooper PJ, Byrnes CA, Francis PW, Robertson CF, Hume DA, Borchers CH, Wainwright CE, Wainwright BJ (2007) Novel neutrophil-derived proteins in bronchoalveolar lavage fluid indicate an exaggerated inflammatory response in pediatric cystic fibrosis patients. Clin Chem 53:1782–1791View ArticlePubMedGoogle Scholar
  61. Ranganathan SC, Parsons F, Gangell C, Brennan S, Stick SM, Sly PD, Australian Respiratory Early Surveillance Team for Cystic Fibrosis (2011) Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis. Thorax 66:408–413View ArticlePubMedGoogle Scholar
  62. Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, Murray CP, Stick SM, Australian Respiratory Early Surveillance Team for Cystic Fibrosis (2013) Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 368:1963–1970View ArticlePubMedGoogle Scholar
  63. Garratt LW, Sutanto EN, Ling KM, Looi K, Iosifidis T, Martinovich KM, Shaw NC, Buckley AG, Kicic-Starcevich E, Lannigan FJ, Knight DA, Stick SM, Kicic A, Australian Respiratory Early Surveillance Team for Cystic Fibrosis (2016) Alpha-1 antitrypsin mitigates the inhibition of airway epithelial cell repair by neutrophil elastase. Am J Respir Cell Mol Biol 54:341–349View ArticlePubMedGoogle Scholar
  64. Schulenburg C, Faccio G, Jankowska D, Maniura-Weber K, Richter M (2016) A FRET-based biosensor for the detection of neutrophil elastase. Analyst 141:1645–1648View ArticlePubMedGoogle Scholar
  65. Wagner CJ, Schultz C, Mall MA (2016) Neutrophil elastase and matrix metalloproteinase 12 in cystic fibrosis lung disease. Mol Cell Pediatr 3:25. doi:10.1186/s40348-016-0053-7 View ArticlePubMedPubMed CentralGoogle Scholar
  66. Jerke U, Hernandez DP, Beaudette P, Korkmaz B, Dittmar G, Kettritz R (2015) Neutrophil serine proteases exert proteolytic activity on endothelial cells. Kidney Int 88:764–775View ArticlePubMedGoogle Scholar
  67. Garratt LW, Sutanto EN, Ling KM, Looi K, Iosifidis T, Martinovich KM, Shaw NC, Kicic-Starcevich E, Knight DA, Ranganathan S, Stick SM, Kicic A, Australian Respiratory Early Surveillance Team for Cystic Fibrosis (2015) Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis. Eur Respir J 46:384–394View ArticlePubMedGoogle Scholar
  68. Jackson PL, Xu X, Wilson L, Weathington NM, Clancy JP, Blalock JE, Gaggar A (2010) Human neutrophil elastase-mediated cleavage sites of MMP-9 and TIMP-1: Implications to cystic fibrosis proteolytic dysfunction. Mol Med 16:159–166PubMedPubMed CentralGoogle Scholar
  69. Tirouvanziam R, Gernez Y, Conrad CK, Moss RB, Schrijver I, Dunn CE, Davies ZA, Herzenberg LA, Herzenberg LA (2008) Profound functional and signaling changes in viable inflammatory neutrophils homing to cystic fibrosis airways. Proc Natl Acad Sci U S A 105:4335–4339View ArticlePubMedPubMed CentralGoogle Scholar
  70. Doring G, Goldstein W, Botzenhart K, Kharazmi A, Schiotz PO, Hoiby N, Dasgupta M (1986) Elastase from polymorphonuclear leucocytes: a regulatory enzyme in immune complex disease. Clin Exp Immunol 64:597–605PubMedPubMed CentralGoogle Scholar
  71. Folds JD, Prince H, Spitznagel JK (1978) Limited cleavage of human immunoglobulins by elastase of human neutrophil polymorphonuclear granulocytes. Possible modulator of immune complex disease. Lab Invest 39:313–321PubMedGoogle Scholar
  72. Fick RB Jr, Naegel GP, Squier SU, Wood RE, Gee JB, Reynolds HY (1984) Proteins of the cystic fibrosis respiratory tract. Fragmented immunoglobulin g opsonic antibody causing defective opsonophagocytosis. J Clin Invest 74:236–248View ArticlePubMedPubMed CentralGoogle Scholar
  73. Fick RB Jr, Naegel GP, Matthay RA, Reynolds HY (1981) Cystic fibrosis Pseudomonas opsonins. Inhibitory nature in an in vitro phagocytic assay. J Clin Invest 68:899–914View ArticlePubMedPubMed CentralGoogle Scholar
  74. Kolb G, Koppler H, Gramse M, Havemann K (1982) Cleavage of IgG by elastase-like protease (ELP) of human polymorphonuclear leukocytes (PMN): isolation and characterization of Fab and Fc fragments and low-molecular-weight peptides. Stimulation of granulocyte function by ELP-derived Fab and Fc fragments. Immunobiology 161:507–523View ArticlePubMedGoogle Scholar
  75. Fick RB Jr, Baltimore RS, Squier SU, Reynolds HY (1985) IgG proteolytic activity of Pseudomonas aeruginosa in cystic fibrosis. J Infect Dis 151:589–598View ArticlePubMedGoogle Scholar
  76. Carevic M, Oz H, Fuchs K, Laval J, Schroth C, Frey N, Hector A, Bilich T, Haug M, Schmidt A, Autenrieth SE, Bucher K, Beer-Hammer S, Gaggar A, Kneilling M, Benarafa C, Gao JL, Murphy PM, Schwarz S, Moepps B, Hartl D (2016) CXCR1 regulates pulmonary anti-Pseudomonas host defense. J Innate Immun 8:362–373View ArticlePubMedGoogle Scholar
  77. Valderrey AD, Pozuelo MJ, Jimenez PA, Macia MD, Oliver A, Rotger R (2010) Chronic colonization by Pseudomonas aeruginosa of patients with obstructive lung diseases: cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. Diagn Microbiol Infect Dis 68:20–27View ArticlePubMedGoogle Scholar
  78. Rutter WC, Burgess DR, Burgess DS (2016) Increasing incidence of multidrug resistance among cystic fibrosis respiratory bacterial isolates. Microb Drug Resist doi: 10.1089/mdr.2016.0048
  79. Winstanley C, O’Brien S, Brockhurst MA (2016) Pseudomonas aeruginosa evolutionary adaptation and diversification in cystic fibrosis chronic lung infections. Trends Microbiol 24:327–337View ArticlePubMedPubMed CentralGoogle Scholar
  80. Wakeman CA, Moore JL, Noto MJ, Zhang Y, Singleton MD, Prentice BM, Gilston BA, Doster RS, Gaddy JA, Chazin WJ, Caprioli RM, Skaar EP (2016) The innate immune protein calprotectin promotes Pseudomonas aeruginosa and Staphylococcus aureus interaction. Nat Commun 7:11951View ArticlePubMedPubMed CentralGoogle Scholar
  81. Sonawane A, Jyot J, During R, Ramphal R (2006) Neutrophil elastase, an innate immunity effector molecule, represses flagellin transcription in Pseudomonas aeruginosa. Infect Immun 74:6682–6689View ArticlePubMedPubMed CentralGoogle Scholar
  82. Hartl D, Latzin P, Hordijk P, Marcos V, Rudolph C, Woischnik M, Krauss-Etschmann S, Koller B, Reinhardt D, Roscher AA, Roos D, Griese M (2007) Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med 13:1423–1430View ArticlePubMedGoogle Scholar
  83. Walsh DE, Greene CM, Carroll TP, Taggart CC, Gallagher PM, O’Neill SJ, McElvaney NG (2001) Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. J Biol Chem 276:35494–35499View ArticlePubMedGoogle Scholar
  84. Padrines M, Wolf M, Walz A, Baggiolini M (1994) Interleukin-8 processing by neutrophil elastase, cathepsin g and proteinase-3. FEBS Lett 352:231–235View ArticlePubMedGoogle Scholar
  85. Baggiolini M, Moser B, Clark-Lewis I (1994) Interleukin-8 and related chemotactic cytokines. The Giles Filley lecture. Chest 105:95S–98SView ArticlePubMedGoogle Scholar
  86. Leavell KJ, Peterson MW, Gross TJ (1997) Human neutrophil elastase abolishes interleukin-8 chemotactic activity. J Leukoc Biol 61:361–366PubMedGoogle Scholar
  87. Morris MR, Doull IJ, Dewitt S, Hallett MB (2005) Reduced iC3b-mediated phagocytotic capacity of pulmonary neutrophils in cystic fibrosis. Clin Exp Immunol 142:68–75View ArticlePubMedPubMed CentralGoogle Scholar
  88. Painter RG, Valentine VG, Lanson NA Jr, Leidal K, Zhang Q, Lombard G, Thompson C, Viswanathan A, Nauseef WM, Wang G, Wang G (2006) CFTR expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry 45:10260–10269View ArticlePubMedPubMed CentralGoogle Scholar
  89. Aiken ML, Painter RG, Zhou Y, Wang G (2012) Chloride transport in functionally active phagosomes isolated from human neutrophils. Free Radic Biol Med 53:2308–2317View ArticlePubMedGoogle Scholar
  90. Lavelle GM, White MM, Browne N, McElvaney NG, Reeves EP (2016) Animal models of cystic fibrosis pathology: phenotypic parallels and divergences. Biomed Res Int 2016:5258727View ArticlePubMedPubMed CentralGoogle Scholar
  91. Tirouvanziam R, de Bentzmann S, Hubeau C, Hinnrasky J, Jacquot J, Peault B, Puchelle E (2000) Inflammation and infection in naive human cystic fibrosis airway grafts. Am J Respir Cell Mol Biol 23:121–127View ArticlePubMedGoogle Scholar
  92. Oceandy D, McMorran BJ, Smith SN, Schreiber R, Kunzelmann K, Alton EW, Hume DA, Wainwright BJ (2002) Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities. Hum Mol Genet 11:1059–1067View ArticlePubMedGoogle Scholar
  93. Bonfield TL, Hodges CA, Cotton CU, Drumm ML (2012) Absence of the cystic fibrosis transmembrane regulator (CFTR) from myeloid-derived cells slows resolution of inflammation and infection. J Leukoc Biol 92:1111–1122View ArticlePubMedPubMed CentralGoogle Scholar
  94. Young RL, Malcolm KC, Kret JE, Caceres SM, Poch KR, Nichols DP, Taylor-Cousar JL, Saavedra MT, Randell SH, Vasil ML, Burns JL, Moskowitz SM, Nick JA (2011) Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa: Evidence of acquired resistance within the CF airway, independent of CFTR. PLoS One 6:e23637View ArticlePubMedPubMed CentralGoogle Scholar
  95. Stockley JA, Walton GM, Lord JM, Sapey E (2013) Aberrant neutrophil functions in stable chronic obstructive pulmonary disease: the neutrophil as an immunotherapeutic target. Int Immunopharmacol 17:1211–1217View ArticlePubMedGoogle Scholar
  96. Bergin DA, Hurley K, Mehta A, Cox S, Ryan D, O’Neill SJ, Reeves EP, McElvaney NG (2013) Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis. J Inflamm Res 6:1–11PubMedPubMed CentralGoogle Scholar
  97. Le Gars M, Descamps D, Roussel D, Saussereau E, Guillot L, Ruffin M, Tabary O, Hong SS, Boulanger P, Paulais M, Malleret L, Belaaouaj A, Edelman A, Huerre M, Chignard M, Sallenave JM (2013) Neutrophil elastase degrades cystic fibrosis transmembrane conductance regulator via calpains and disables channel function in vitro and in vivo. Am J Respir Crit Care Med 187:170–179View ArticlePubMedGoogle Scholar
  98. Pohl K, Hayes E, Keenan J, Henry M, Meleady P, Molloy K, Jundi B, Bergin DA, McCarthy C, McElvaney OJ, White MM, Clynes M, Reeves EP, McElvaney NG (2014) A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood 124:999–1009View ArticlePubMedPubMed CentralGoogle Scholar
  99. Mocsai A (2013) Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med 210:1283–1299View ArticlePubMedPubMed CentralGoogle Scholar
  100. Powell DR, Huttenlocher A (2016) Neutrophils in the tumor microenvironment. Trends Immunol 37:41–52View ArticlePubMedGoogle Scholar
  101. Sionov RV, Fridlender ZG, Granot Z (2015) The multifaceted roles neutrophils play in the tumor microenvironment. Cancer Microenviron 8:125–158View ArticlePubMedGoogle Scholar
  102. Jones HR, Robb CT, Perretti M, Rossi AG (2016) The role of neutrophils in inflammation resolution. Semin Immunol 28:137–145View ArticlePubMedGoogle Scholar
  103. Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531View ArticlePubMedGoogle Scholar
  104. Norian LA, Rodriguez PC, O’Mara LA, Zabaleta J, Ochoa AC, Cella M, Allen PM (2009) Tumor-infiltrating regulatory dendritic cells inhibit CD8+ t cell function via L-arginine metabolism. Cancer Res 69:3086–3094View ArticlePubMedPubMed CentralGoogle Scholar
  105. Burrack KS, Tan JJ, McCarthy MK, Her Z, Berger JN, Ng LF, Morrison TE (2015) Myeloid cell Arg1 inhibits control of arthritogenic alphavirus infection by suppressing antiviral T cells. PLoS Pathog 11:e1005191View ArticlePubMedPubMed CentralGoogle Scholar
  106. Ingersoll SA, Laval J, Forrest OA, Preininger M, Brown MR, Arafat D, Gibson G, Tangpricha V, Tirouvanziam R (2015) Mature cystic fibrosis airway neutrophils suppress T cell function: evidence for a role of arginase 1 but not programmed death-ligand 1. J Immunol 194:5520–5528View ArticlePubMedPubMed CentralGoogle Scholar
  107. Doring G, Frank F, Boudier C, Herbert S, Fleischer B, Bellon G (1995) Cleavage of lymphocyte surface antigens CD2, CD4, and CD8 by polymorphonuclear leukocyte elastase and cathepsin G in patients with cystic fibrosis. J Immunol 154:4842–4850PubMedGoogle Scholar
  108. Bank U, Reinhold D, Schneemilch C, Kunz D, Synowitz HJ, Ansorge S (1999) Selective proteolytic cleavage of IL-2 receptor and IL-6 receptor ligand binding chains by neutrophil-derived serine proteases at foci of inflammation. J Interferon Cytokine Res 19:1277–1287View ArticlePubMedGoogle Scholar
  109. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8:239–245View ArticlePubMedGoogle Scholar
  110. De Fanis U, Mori F, Kurnat RJ, Lee WK, Bova M, Adkinson NF, Casolaro V (2007) GATA3 up-regulation associated with surface expression of CD294/CRTh2: a unique feature of human Th2 cells. Blood 109:4343–4350View ArticlePubMedPubMed CentralGoogle Scholar
  111. Kushwah R, Gagnon S, Sweezey NB (2013) Intrinsic predisposition of naive cystic fibrosis T cells to differentiate towards a Th17 phenotype. Respir Res 14:138View ArticlePubMedPubMed CentralGoogle Scholar
  112. Mulcahy EM, Hudson JB, Beggs SA, Reid DW, Roddam LF, Cooley MA (2015) High peripheral blood Th17 percent associated with poor lung function in cystic fibrosis. PLoS One 10:e0120912View ArticlePubMedPubMed CentralGoogle Scholar
  113. Hector A, Schafer H, Poschel S, Fischer A, Fritzsching B, Ralhan A, Carevic M, Oz H, Zundel S, Hogardt M, Bakele M, Rieber N, Riethmueller J, Graepler-Mainka U, Stahl M, Bender A, Frick JS, Mall M, Hartl D (2015) Regulatory T-cell impairment in cystic fibrosis patients with chronic Pseudomonas infection. Am J Respir Crit Care Med 191:914–923View ArticlePubMedGoogle Scholar
  114. Tan HL, Regamey N, Brown S, Bush A, Lloyd CM, Davies JC (2011) The Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit Care Med 184:252–258View ArticlePubMedPubMed CentralGoogle Scholar
  115. Tiringer K, Treis A, Fucik P, Gona M, Gruber S, Renner S, Dehlink E, Nachbaur E, Horak F, Jaksch P, Doring G, Crameri R, Jung A, Rochat MK, Hormann M, Spittler A, Klepetko W, Akdis CA, Szepfalusi Z, Frischer T, Eiwegger T (2013) A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 187:621–629View ArticlePubMedGoogle Scholar
  116. Singhal S, Bhojnagarwala PS, O’Brien S, Moon EK, Garfall AL, Rao AS, Quatromoni JG, Stephen TL, Litzky L, Deshpande C, Feldman MD, Hancock WW, Conejo-Garcia JR, Albelda SM, Eruslanov EB (2016) Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 30:120–135View ArticlePubMedGoogle Scholar
  117. Trentini MM, de Oliveira FM, Kipnis A, Junqueira-Kipnis AP (2016) The role of neutrophils in the induction of specific Th1 and Th17 during vaccination against tuberculosis. Front Microbiol 7:898View ArticlePubMedPubMed CentralGoogle Scholar
  118. Nembrini C, Marsland BJ, Kopf M (2009) IL-17-producing T cells in lung immunity and inflammation. J Allergy Clin Immunol 123:986–994View ArticlePubMedGoogle Scholar
  119. Wright HL, Moots RJ, Edwards SW (2014) The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol 10:593–601View ArticlePubMedGoogle Scholar
  120. Elphick HE, Mallory G (2013) Oxygen therapy for cystic fibrosis. Cochrane Database Syst Rev:CD003884
  121. Iannitti RG, Casagrande A, De Luca A, Cunha C, Sorci G, Riuzzi F, Borghi M, Galosi C, Massi-Benedetti C, Oury TD, Cariani L, Russo M, Porcaro L, Colombo C, Majo F, Lucidi V, Fiscarelli E, Ricciotti G, Lass-Florl C, Ratclif L, Esposito A, De Benedictis FM, Donato R, Carvalho A, Romani L (2013) Hypoxia promotes danger-mediated inflammation via receptor for advanced glycation end products in cystic fibrosis. Am J Respir Crit Care Med 188:1338–1350View ArticlePubMedGoogle Scholar
  122. Tabcharani JA, Rommens JM, Hou YX, Chang XB, Tsui LC, Riordan JR, Hanrahan JW (1993) Multi-ion pore behaviour in the CFTR chloride channel. Nature 366:79–82View ArticlePubMedGoogle Scholar
  123. Gould NS, Gauthier S, Kariya CT, Min E, Huang J, Brian DJ (2010) Hypertonic saline increases lung epithelial lining fluid glutathione and thiocyanate: Two protective CFTR dependent thiols against oxidative injury. Respir Res 11:119View ArticlePubMedPubMed CentralGoogle Scholar
  124. Chandler JD, Min E, Huang J, McElroy CS, Dickerhof N, Mocatta T, Fletcher AA, Evans CM, Liang L, Patel M, Kettle AJ, Nichols DP, Day BJ (2015) Antiinflammatory and antimicrobial effects of thiocyanate in a cystic fibrosis mouse model. Am J Respir Cell Mol Biol 53:193–205View ArticlePubMedPubMed CentralGoogle Scholar
  125. Duranton C, Rubera I, Cougnon M, Melis N, Chargui A, Mograbi B, Tauc M (2012) CFTR is involved in the fine tuning of intracellular redox status: physiological implications in cystic fibrosis. Am J Pathol 181:1367–1377View ArticlePubMedGoogle Scholar
  126. Rotoli BM, Bussolati O, Sironi M, Cabrini G, Gazzola GC (1994) CFTR protein is involved in the efflux of neutral amino acids. Biochem Biophys Res Commun 204:653–658View ArticlePubMedGoogle Scholar
  127. Picher M (2011) Mechanisms regulating airway nucleotides. Subcell Biochem 55:17–49View ArticlePubMedGoogle Scholar
  128. Mager S, Sloan J (2003) Possible role of amino acids, peptides, and sugar transporter in protein removal and innate lung defense. Eur J Pharmacol 479:263–267View ArticlePubMedGoogle Scholar
  129. Thomson E, Brennan S, Senthilmohan R, Gangell CL, Chapman AL, Sly PD, Kettle AJ, Australian Respiratory Early Surveillance Team for Cystic Fibrosis, Balding E, Berry LJ, Carlin JB, Carzino R, de Klerk N, Douglas T, Foo C, Garratt LW, Hall GL, Harrison J, Kicic A, Laing IA, Logie KM, Massie J, Mott LS, Murray C, Parsons F, Pillarisetti N, Poreddy SR, Ranganathan SC, Robertson CF, Robins-Browne R, Robinson PJ, Skoric B, Stick SM, Sutanto EN, Williamson E (2010) Identifying peroxidases and their oxidants in the early pathology of cystic fibrosis. Free Radic Biol Med 49:1354–1360View ArticlePubMedGoogle Scholar
  130. Corti A, Franzini M, Cianchetti S, Bergamini G, Lorenzini E, Melotti P, Paolicchi A, Paggiaro P, Pompella A (2012) Contribution by polymorphonucleate granulocytes to elevated gamma-glutamyltransferase in cystic fibrosis sputum. PLoS One 7:e34772View ArticlePubMedPubMed CentralGoogle Scholar
  131. Grasemann H, Schwiertz R, Matthiesen S, Racke K, Ratjen F (2005) Increased arginase activity in cystic fibrosis airways. Am J Respir Crit Care Med 172:1523–1528View ArticlePubMedGoogle Scholar
  132. Jacobsen LC, Theilgaard-Monch K, Christensen EI, Borregaard N (2007) Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils. Blood 109:3084–3087PubMedGoogle Scholar
  133. Grasemann H, Ratjen F (2012) Nitric oxide and L-arginine deficiency in cystic fibrosis. Curr Pharm Des 18:726–736View ArticlePubMedGoogle Scholar
  134. Grasemann H, Shehnaz D, Enomoto M, Leadley M, Belik J, Ratjen F (2012) L-ornithine derived polyamines in cystic fibrosis airways. PLoS One 7:e46618View ArticlePubMedPubMed CentralGoogle Scholar
  135. Laval J, Touhami J, Herzenberg LA, Conrad C, Taylor N, Battini JL, Sitbon M, Tirouvanziam R (2013) Metabolic adaptation of neutrophils in cystic fibrosis airways involves distinct shifts in nutrient transporter expression. J Immunol 190:6043–6050View ArticlePubMedGoogle Scholar
  136. Jiang K, Sun X, Chen Y, Shen Y, Jarvis JN (2015) RNA sequencing from human neutrophils reveals distinct transcriptional differences associated with chronic inflammatory states. BMC Med Genomics 8:55View ArticlePubMedPubMed CentralGoogle Scholar
  137. Zimmermann M, Aguilera FB, Castellucci M, Rossato M, Costa S, Lunardi C, Ostuni R, Girolomoni G, Natoli G, Bazzoni F, Tamassia N, Cassatella MA (2015) Chromatin remodelling and autocrine TNFalpha are required for optimal interleukin-6 expression in activated human neutrophils. Nat Commun 6:6061View ArticlePubMedGoogle Scholar
  138. Downey DG, Martin SL, Dempster M, Moore JE, Keogan MT, Starcher B, Edgar J, Bilton D, Elborn JS (2007) The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis. Pediatr Pulmonol 42:216–220View ArticlePubMedGoogle Scholar
  139. Giacchi V, Rotolo N, Amato B, Di Dio G, Betta P, La Rosa M, Leonardi S, Sciacca P (2015) Heart involvement in children and adults with cystic fibrosis: correlation with pulmonary indexes and inflammation markers. Heart Lung Circ 24:1002–1010View ArticlePubMedGoogle Scholar
  140. Reverri EJ, Morrissey BM, Cross CE, Steinberg FM (2014) Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis. Free Radic Biol Med 76:261–277View ArticlePubMedGoogle Scholar
  141. Simoneau T, Bazzaz O, Sawicki GS, Gordon C (2014) Vitamin D status in children with cystic fibrosis. Associations with inflammation and bacterial colonization. Ann Am Thorac Soc 11:205–210View ArticlePubMedGoogle Scholar
  142. Kocarnik JM, Chan AT, Slattery ML, Potter JD, Meyerhardt J, Phipps A, Nan H, Harrison T, Rohan TE, Qi L, Hou L, Caan B, Kroenke CH, Strickler H, Hayes RB, Schoen RE, Chong DQ, White E, Berndt SI, Peters U, Newcomb PA (2016) Relationship of prediagnostic body mass index with survival after colorectal cancer: Stage-specific associations. Int J Cancer 139:1065–1072View ArticlePubMedGoogle Scholar
  143. Fournier BM, Parkos CA (2012) The role of neutrophils during intestinal inflammation. Mucosal Immunol 5:354–366View ArticlePubMedGoogle Scholar
  144. Maloy KJ, Powrie F (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474:298–306View ArticlePubMedGoogle Scholar
  145. Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621View ArticlePubMedPubMed CentralGoogle Scholar
  146. Molloy MJ, Grainger JR, Bouladoux N, Hand TW, Koo LY, Naik S, Quinones M, Dzutsev AK, Gao JL, Trinchieri G, Murphy PM, Belkaid Y (2013) Intraluminal containment of commensal outgrowth in the gut during infection-induced dysbiosis. Cell Host Microbe 14:318–328View ArticlePubMedPubMed CentralGoogle Scholar
  147. Kragh KN, Alhede M, Jensen PO, Moser C, Scheike T, Jacobsen CS, Seier Poulsen S, Eickhardt-Sorensen SR, Trostrup H, Christoffersen L, Hougen HP, Rickelt LF, Kuhl M, Hoiby N, Bjarnsholt T (2014) Polymorphonuclear leukocytes restrict growth of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. Infect Immun 82:4477–4486View ArticlePubMedPubMed CentralGoogle Scholar
  148. Masri S, Papagiannakopoulos T, Kinouchi K, Liu Y, Cervantes M, Baldi P, Jacks T, Sassone-Corsi P (2016) Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cell 165:896–909View ArticlePubMedGoogle Scholar
  149. Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW (2014) Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 190:175–184View ArticlePubMedPubMed CentralGoogle Scholar
  150. Konstan MW, Byard PJ, Hoppel CL, Davis PB (1995) Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 332:848–854View ArticlePubMedGoogle Scholar
  151. Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV (1995) A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic fibrosis foundation prednisone trial group. J Pediatr 126:515–523View ArticlePubMedGoogle Scholar
  152. Lai HC, FitzSimmons SC, Allen DB, Kosorok MR, Rosenstein BJ, Campbell PW, Farrell PM (2000) Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N Engl J Med 342:851–859View ArticlePubMedGoogle Scholar
  153. Konstan MW, Doring G, Heltshe SL, Lands LC, Hilliard KA, Koker P, Bhattacharya S, Staab A, Hamilton A, Investigators, Coordinators of BIT (2014) A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis. J Cyst Fibros 13:148–155View ArticlePubMedPubMed CentralGoogle Scholar
  154. Moss RB, Mistry SJ, Konstan MW, Pilewski JM, Kerem E, Tal-Singer R, Lazaar AL, Investigators CF (2013) Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros 12:241–248View ArticlePubMedGoogle Scholar
  155. Doring G, Bragonzi A, Paroni M, Akturk FF, Cigana C, Schmidt A, Gilpin D, Heyder S, Born T, Smaczny C, Kohlhaufl M, Wagner TO, Loebinger MR, Bilton D, Tunney MM, Elborn JS, Pier GB, Konstan MW, Ulrich M (2014) BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs. J Cyst Fibros 13:156–163View ArticlePubMedGoogle Scholar
  156. Lee E, Lindo T, Jackson N, Meng-Choong L, Reynolds P, Hill A, Haswell M, Jackson S, Kilfeather S (1999) Reversal of human neutrophil survival by leukotriene B(4) receptor blockade and 5-lipoxygenase and 5-lipoxygenase activating protein inhibitors. Am J Respir Crit Care Med 160:2079–2085View ArticlePubMedGoogle Scholar
  157. Kelly E, Greene CM, McElvaney NG (2008) Targeting neutrophil elastase in cystic fibrosis. Expert Opin Ther Targets 12:145–157View ArticlePubMedGoogle Scholar
  158. Geraghty P, Rogan MP, Greene CM, Brantly ML, O’Neill SJ, Taggart CC, McElvaney NG (2008) Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro. Thorax 63:621–626View ArticlePubMedGoogle Scholar
  159. Guyot N, Butler MW, McNally P, Weldon S, Greene CM, Levine RL, O’Neill SJ, Taggart CC, McElvaney NG (2008) Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis. J Biol Chem 283:32377–32385View ArticlePubMedPubMed CentralGoogle Scholar
  160. Forde E, Humphreys H, Greene CM, Fitzgerald-Hughes D, Devocelle M (2014) Potential of host defense peptide prodrugs as neutrophil elastase-dependent anti-infective agents for cystic fibrosis. Antimicrob Agents Chemother 58:978–985View ArticlePubMedPubMed CentralGoogle Scholar
  161. Wittamer V, Bondue B, Guillabert A, Vassart G, Parmentier M, Communi D (2005) Neutrophil-mediated maturation of chemerin: a link between innate and adaptive immunity. J Immunol 175:487–493View ArticlePubMedGoogle Scholar
  162. Le-Barillec K, Si-Tahar M, Balloy V, Chignard M (1999) Proteolysis of monocyte cd14 by human leukocyte elastase inhibits lipopolysaccharide-mediated cell activation. J Clin Invest 103:1039–1046View ArticlePubMedPubMed CentralGoogle Scholar
  163. Macleod T, Doble R, McGonagle D, Wasson CW, Alase A, Stacey M, Wittmann M (2016) Neutrophil elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 receptor antagonist. Sci Rep 6:24880. doi:10.1038/srep24880 View ArticlePubMedPubMed CentralGoogle Scholar
  164. Tosi MF, Zakem H (1992) Surface expression of Fc gamma receptor III (CD16) on chemoattractant-stimulated neutrophils is determined by both surface shedding and translocation from intracellular storage compartments. J Clin Invest 90:462–470View ArticlePubMedPubMed CentralGoogle Scholar
  165. Remold-O’Donnell E, Parent D (1995) Specific sensitivity of CD43 to neutrophil elastase. Blood 86:2395–2402PubMedGoogle Scholar
  166. Ryu OH, Choi SJ, Firatli E, Choi SW, Hart PS, Shen RF, Wang G, Wu WW, Hart TC (2005) Proteolysis of macrophage inflammatory protein-1alpha isoforms ld78beta and ld78alpha by neutrophil-derived serine proteases. J Biol Chem 280:17415–17421View ArticlePubMedGoogle Scholar
  167. Zhao P, Lieu T, Barlow N, Sostegni S, Haerteis S, Korbmacher C, Liedtke W, Jimenez-Vargas NN, Vanner SJ, Bunnett NW (2015) Neutrophil elastase activates protease-activated receptor-2 (PAR-2) and transient receptor potential vanilloid 4 (TRPV4) to cause inflammation and pain. J Biol Chem 290:13875–13887View ArticlePubMedPubMed CentralGoogle Scholar
  168. Cumashi A, Ansuini H, Celli N, De Blasi A, O’Brien PJ, Brass LF, Molino M (2001) Neutrophil proteases can inactivate human PAR-3 and abolish the co-receptor function of PAR-3 on murine platelets. Thromb Haemost 85:533–538PubMedGoogle Scholar
  169. van den Berg CW, Tambourgi DV, Clark HW, Hoong SJ, Spiller OB, McGreal EP (2014) Mechanism of neutrophil dysfunction: neutrophil serine proteases cleave and inactivate the C5a receptor. J Immunol 192:1787–1795View ArticlePubMedGoogle Scholar
  170. Vogt W (2000) Cleavage of the fifth component of complement and generation of a functionally active C5b6-like complex by human leukocyte elastase. Immunobiology 201:470–477View ArticlePubMedGoogle Scholar
  171. Taylor JC, Crawford IP, Hugli TE (1977) Limited degradation of the third component (C3) of human complement by human leukocyte elastase (HLE): partial characterization of C3 fragments. Biochemistry 16:3390–3396View ArticlePubMedGoogle Scholar
  172. Tosi MF, Zakem H, Berger M (1990) Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J Clin Invest 86:300–308View ArticlePubMedPubMed CentralGoogle Scholar
  173. Alfaidi M, Wilson H, Daigneault M, Burnett A, Ridger V, Chamberlain J, Francis S (2015) Neutrophil elastase promotes interleukin-1beta secretion from human coronary endothelium. J Biol Chem 290:24067–24078View ArticlePubMedPubMed CentralGoogle Scholar
  174. Rao RM, Betz TV, Lamont DJ, Kim MB, Shaw SK, Froio RM, Baleux F, Arenzana-Seisdedos F, Alon R, Luscinskas FW (2004) Elastase release by transmigrating neutrophils deactivates endothelial-bound SDF-1alpha and attenuates subsequent t lymphocyte transendothelial migration. J Exp Med 200:713–724View ArticlePubMedPubMed CentralGoogle Scholar
  175. Wada Y, Yoshida K, Tsutani Y, Shigematsu H, Oeda M, Sanada Y, Suzuki T, Mizuiri H, Hamai Y, Tanabe K, Ukon K, Hihara J (2007) Neutrophil elastase induces cell proliferation and migration by the release of TGF-alpha, PDGF and VEGF in esophageal cell lines. Oncol Rep 17:161–167PubMedGoogle Scholar
  176. Bank U, Kupper B, Ansorge S (2000) Inactivation of interleukin-6 by neutrophil proteases at sites of inflammation. Protective effects of soluble il-6 receptor chains. Adv Exp Med Biol 477:431–437View ArticlePubMedGoogle Scholar
  177. McGreal EP, Davies PL, Powell W, Rose-John S, Spiller OB, Doull I, Jones SA, Kotecha S (2010) Inactivation of il-6 and soluble il-6 receptor by neutrophil derived serine proteases in cystic fibrosis. Biochim Biophys Acta 1802:649–658View ArticlePubMedGoogle Scholar
  178. Ungurs MJ, Sinden NJ, Stockley RA (2014) Progranulin is a substrate for neutrophil-elastase and proteinase-3 in the airway and its concentration correlates with mediators of airway inflammation in COPD. Am J Physiol Lung Cell Mol Physiol 306:L80–L87View ArticlePubMedGoogle Scholar
  179. Kessenbrock K, Frohlich L, Sixt M, Lammermann T, Pfister H, Bateman A, Belaaouaj A, Ring J, Ollert M, Fassler R, Jenne DE (2008) Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest 118:2438–2447PubMedPubMed CentralGoogle Scholar
  180. Vega-Carrascal I, Reeves EP, Niki T, Arikawa T, McNally P, O’Neill SJ, Hirashima M, McElvaney NG (2011) Dysregulation of TIM-3/galectin-9 pathway in the cystic fibrosis airways. J Immunol 186:2897–2909View ArticlePubMedGoogle Scholar
  181. Nunes GL, Simoes A, Dyszy FH, Shida CS, Juliano MA, Juliano L, Gesteira TF, Nader HB, Murphy G, Chaffotte AF, Goldberg ME, Tersariol IL, Almeida PC (2011) Mechanism of heparin acceleration of tissue inhibitor of metalloproteases-1 (TIMP-1) degradation by the human neutrophil elastase. PLoS One 6:e21525View ArticlePubMedPubMed CentralGoogle Scholar
  182. Si-Tahar M, Pidard D, Balloy V, Moniatte M, Kieffer N, Van Dorsselaer A, Chignard M (1997) Human neutrophil elastase proteolytically activates the platelet integrin alpha2bbeta3 through cleavage of the carboxyl terminus of the alpha2b subunit heavy chain. Involvement in the potentiation of platelet aggregation. J Biol Chem 272:11636–11647View ArticlePubMedGoogle Scholar
  183. Carden D, Xiao F, Moak C, Willis BH, Robinson-Jackson S, Alexander S (1998) Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins. Am J Physiol Heart Circ Physiol 275:H385–H392Google Scholar
  184. DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, Panchenko MP (2002) Elastase-released epidermal growth factor recruits epidermal growth factor receptor and extracellular signal-regulated kinases to down-regulate tropoelastin mRNA in lung fibroblasts. J Biol Chem 277:18938–18946View ArticlePubMedGoogle Scholar
  185. Chua F, Laurent GJ (2006) Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proc Am Thorac Soc 3:424–427View ArticlePubMedGoogle Scholar
  186. Adebamiro A, Cheng Y, Rao US, Danahay H, Bridges RJ (2007) A segment of gamma ENaC mediates elastase activation of Na + transport. J Gen Physiol 130:611–629View ArticlePubMedPubMed CentralGoogle Scholar
  187. Caldwell RA, Boucher RC, Stutts MJ (2005) Neutrophil elastase activates near-silent epithelial Na + channels and increases airway epithelial Na + transport. Am J Physiol Lung Cell Mol Physiol 288:L813–L819View ArticlePubMedGoogle Scholar
  188. Fischer BM, Domowicz DA, Zheng S, Carter JL, McElvaney NG, Taggart C, Lehmann JR, Voynow JA, Ghio AJ (2009) Neutrophil elastase increases airway epithelial nonheme iron levels. Clin Transl Sci 2:333–339View ArticlePubMedPubMed CentralGoogle Scholar
  189. Klingemann HG, Egbring R, Holst F, Gramse M, Havemann K (1982) Degradation of human plasma fibrin stabilizing factor XIII subunits by human granulocytic proteinases. Thromb Res 28:793–801View ArticlePubMedGoogle Scholar
  190. Liau DF, Yin NX, Huang J, Ryan SF (1996) Effects of human polymorphonuclear leukocyte elastase upon surfactant proteins in vitro. Biochim Biophys Acta 1302:117–128View ArticlePubMedGoogle Scholar
  191. Cooley J, McDonald B, Accurso FJ, Crouch EC, Remold-O’Donnell E (2008) Patterns of neutrophil serine protease-dependent cleavage of surfactant protein d in inflammatory lung disease. J Leukoc Biol 83:946–955View ArticlePubMedGoogle Scholar
  192. Lee KH, Lee CH, Jeong J, Jang AH, Yoo CG (2015) Neutrophil elastase differentially regulates interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) production by cigarette smoke extract. J Biol Chem 290:28438–28445View ArticlePubMedPubMed CentralGoogle Scholar
  193. Griffin S, Taggart CC, Greene CM, O’Neill S, McElvaney NG (2003) Neutrophil elastase up-regulates human beta-defensin-2 expression in human bronchial epithelial cells. FEBS Lett 546:233–236View ArticlePubMedGoogle Scholar
  194. Geraghty P, Rogan MP, Greene CM, Boxio RM, Poiriert T, O’Mahony M, Belaaouaj A, O’Neill SJ, Taggart CC, McElvaney NG (2007) Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression. J Immunol 178:5871–5878View ArticlePubMedGoogle Scholar
  195. Yamaguchi R, Yamamoto T, Sakamoto A, Narahara S, Sugiuchi H, Yamaguchi Y (2016) Neutrophil elastase enhances IL-12p40 production by lipopolysaccharide-stimulated macrophages via transactivation of the PAR-2/EGFR/TLR4 signaling pathway. Blood Cells Mol Dis 59:1–7View ArticlePubMedGoogle Scholar
  196. Chen HC, Lin HC, Liu CY, Wang CH, Hwang T, Huang TT, Lin CH, Kuo HP (2004) Neutrophil elastase induces IL-8 synthesis by lung epithelial cells via the mitogen-activated protein kinase pathway. J Biomed Sci 11:49–58View ArticlePubMedGoogle Scholar
  197. Devaney JM, Greene CM, Taggart CC, Carroll TP, O’Neill SJ, McElvaney NG (2003) Neutrophil elastase up-regulates interleukin-8 via Toll-like receptor 4. FEBS Lett 544:129–132View ArticlePubMedGoogle Scholar
  198. Chawla A, Alatrash G, Philips AV, Qiao N, Sukhumalchandra P, Kerros C, Diaconu I, Gall V, Neal S, Peters HL, Clise-Dwyer K, Molldrem JJ, Mittendorf EA (2016) Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells. Cancer Immunol Immunother 65:741–751View ArticlePubMedGoogle Scholar
  199. Kohri K, Ueki IF, Nadel JA (2002) Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation. Am J Physiol Lung Cell Mol Physiol 283:L531–L540View ArticlePubMedGoogle Scholar
  200. Shao MX, Nadel JA (2005) Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J Immunol 175:4009–4016View ArticlePubMedGoogle Scholar

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