Skip to main content

The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases


S100A8/A9 and S100A12 are released from activated monocytes and granulocytes and act as proinflammatory endogenous toll-like receptor (TLR)4-ligands. S100 serum concentrations correlate with disease activity, both during local and systemic inflammatory processes. In some autoinflammatory diseases such as familial Mediterranean fever (FMF) or systemic juvenile idiopathic arthritis (SJIA), dysregulation of S100 release may be involved in the pathogenesis. Moreover, S100 serum levels are a valuable supportive tool in the diagnosis of SJIA in fever of unknown origin. Furthermore, S100 levels can be used to monitor disease activity to subclinical level, as their serum concentrations decrease with successful treatment.

Functions of phagocyte-specific S100 proteins

The S100 protein family represents the largest subgroup within the Ca2+-binding EF-hand protein superfamily. Constitutive expression of the phagocyte-specific S100 proteins A8 (also termed calgranulin or myeloid-related protein, MRP8) and A9 (calgranulin B, MRP14) as well as A12 (calgranulin C, MRP6) is largely restricted to granulocytes and monocytes while S100A12 is only expressed by human neutrophils [33].

While a number of different intracellular mechanistic implications have been proposed for S100A8/A9 (reviewed in [2]), very little data suggest an intracellular function of S100A12 (Table 1).

Table 1 Intracellular calgranulin functions

S100A8, A9, and A12 are lacking structural elements required for secretion via the classical endoplasmic reticulum and Golgi-dependent secretory pathway. Thus, one of the primary, though passive, release “mechanisms” involves necrotic cell death. Further, there is evidence for active cytoskeleton-dependent non-classical secretion [5, 27, 32] (Fig. 1), which is similarly used by cytokines such as interleukin (IL)-1 [30].

Fig. 1

DAMP functions of calgranulins. Calgranulins can be released by circulating neutrophils (S100A8/A9 and S100A12) or monocytes (S100A8/A9) upon cellular necrosis or active, non-classical transport. Once, extracellular calgranulins can trigger proinflammatory activation of human monocytes in a toll-like receptor 4 (TLR4)-dependent manner. Via sensors such as the multi-ligand receptor for advanced glycation end products or TLR4, S100A8/A9 and A12 can further induce proinflammatory activation of vascular endothelium, which facilitates leukocyte rolling and subsequent extravasation, and thus promotes tissue inflammation

Once released from cells, the extracellular role of calgranulins as damage-associated molecular patter (DAMP) molecules is potentially most relevant in the context of autoinflammation (Fig. 1). In this respect, a majority of studies limits receptor binding and inflammatory signaling of calgranulins to toll-like receptor 4 (TLR4) [5, 16, 17, 24, 28].

Role of S100 proteins in autoinflammatory diseases

Hypersecretion of S100 proteins can result in a sterile inflammatory environment, which triggers proinflammatory cytokine as well as further S100 expression [9, 15] (Fig. 1). During inflammatory attacks, serum levels of S100 proteins are massively elevated in FMF and the excessive amount of these proteins suggests its involvement in the pathogenesis this disease [9, 11]. Pyrin, which is mutated in FMF, interacts with PSTPIP1, which causes pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) [13]. Especially the latter shows excessively high S100 levels [11]. S100A8 and A9 bind to both the subcellular actin network and microtubules [32], which might link these proteins to pyrin and PSTPIP1. Accordingly, colchicine, which is effective in FMF and blocks tubulin-dependent processes, inhibits alternative secretion of S100 proteins [25].

The predominant role of the innate immune system in SJIA is underscored by high serum concentrations of S100 proteins. These concentrations are closely associated with disease activity and can be found neither in other forms of inflammatory arthritis nor in other autoimmune or infectious diseases [3, 4, 8]. Furthermore, extracellular S100A8 and S100A9 form a positive inflammatory feedback loop with IL-1ß, and depletion of these proteins from SJIA patient’s serum diminishes the IL-1ß-inducing capacity of this serum [7].

In contrast, in the cryopyrin-associated periodic syndromes (CAPS) or periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA) S100 levels are within the range of those found in infectious diseases. Although the exact role of the S100 proteins in CAPS has not yet been fully understood, these proteins are promising markers of IL-1ß-driven inflammation [21]. In PFAPA, S100 proteins are upregulated during flares and are within the range of healthy controls during symptom-free intervals [18].

S100 proteins as biomarkers in clinical practice

Fever of unknown origin (FUO) is a challenging medical problem predominantly caused by infections, malignancies, immunodeficiency syndromes, and autoimmune or autoinflammatory diseases [1]. S100A8/A9 and S100A12 levels can potentially differentiate SJIA from other causes of FUO including systemic infections but not FMF [6, 7, 34]. The third disease group that shows constantly extremely elevated S100 protein serum levels is PAPA/PAMI [11] (Table 2).

Table 2 Serum concentration of phagocyte-specific S100 proteins in systemic inflammatory diseases (adapted and updated from [15])

In patients with an established diagnosis of an autoinflammatory disorder, rapid commencement of effective therapy is essential to avoid damage and complications. In autoinflammatory diseases, acute phase reactants are commonly elevated, including SAA and CRP as markers of inflammation [10]. As a more sensitive biomarker, S100A12 has been demonstrated to reflect clinical disease activity and therapeutic response in MWS [19]. Various states of subclinical disease activity were demonstrated in all types of CAPS, depending on the type of anti-IL-1 therapy. Here, S100A8/A9 proved to be a sensitive biomarker for monitoring disease activity and response to IL-1 blockade [35]. In FMF, S100A12 shows an excellent correlation to disease activity [14, 34]. S100A12 may also allow stratification of FMF patients according to disease severity [9]. Moreover, S100A12 reflects subclinical inflammation in heterozygous carriers of MEFV gene mutations, and patients with well controlled anti-inflammatory treatment have significantly decreased serum levels [22]. The same applies for SJIA, where S100A8/A9 serum concentrations correlate closely with response to treatment and disease activity [12]. In SJIA, S100A8/A9 serum concentrations are the first predictive biomarker indicating subclinical disease activity and stratifying patients at risk of relapse during times of clinically inactive disease [12].

S100A8/A9 and S100A12 can thus be used as surrogate markers not only to monitor therapeutic responses at initiating therapies with the goal of inducing remission, but also during maintenance therapies.


  1. 1.

    Arnow PM, Flaherty JP (1997) Fever of unknown origin. Lancet 350:575–580.

    CAS  Article  Google Scholar 

  2. 2.

    Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL (2013) Functions of S100 proteins. Curr Mol Med 13:24–57

    CAS  Article  Google Scholar 

  3. 3.

    Foell D, Roth J (2004) Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 50:3762–3771.

    CAS  Article  Google Scholar 

  4. 4.

    Foell D et al (2004) Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum 50:1286–1295.

    CAS  Article  Google Scholar 

  5. 5.

    Foell D et al (2013) Proinflammatory S100A12 can activate human monocytes via Toll-like receptor 4. Am J Respir Crit Care Med 187:1324–1334.

    CAS  Article  Google Scholar 

  6. 6.

    Foell D, Wittkowski H, Roth J (2007) Mechanisms of disease: a ‘DAMP’ view of inflammatory arthritis. Nat Clin Pract Rheumatol 3:382–390.

    CAS  Article  Google Scholar 

  7. 7.

    Frosch M, Ahlmann M, Vogl T, Wittkowski H, Wulffraat N, Foell D, Roth J (2009) The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 60:883–891.

    CAS  Article  Google Scholar 

  8. 8.

    Frosch M, Foell D, Ganser G, Roth J (2003) Arthrosonography of hip and knee joints in the follow up of juvenile rheumatoid arthritis. Ann Rheum Dis 62:242–244

    CAS  Article  Google Scholar 

  9. 9.

    Gohar F et al (2016) Correlation of secretory activity of neutrophils with genotype in patients with familial mediterranean fever. Arthritis Rheumatol 68:3010–3022.

    CAS  Article  Google Scholar 

  10. 10.

    Hawkins PN, Lachmann HJ, Aganna E, McDermott MF (2004) Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 50:607–612.

    CAS  Article  Google Scholar 

  11. 11.

    Holzinger D et al (2015) Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. J Allergy Clin Immunol 136:1337–1345.

    CAS  Article  Google Scholar 

  12. 12.

    Holzinger D et al (2012) The Toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis. Ann Rheum Dis 71:974–980.

    CAS  Article  Google Scholar 

  13. 13.

    Holzinger D, Roth J (2016) Alarming consequences - autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1. Curr Opin Rheumatol 28:550–559.

    CAS  Article  Google Scholar 

  14. 14.

    Kallinich T, Wittkowski H, Keitzer R, Roth J, Foell D (2010) Neutrophil-derived S100A12 as novel biomarker of inflammation in familial Mediterranean fever. Ann Rheum Dis 69:677–682.

    Article  Google Scholar 

  15. 15.

    Kessel C, Holzinger D, Foell D (2013) Phagocyte-derived S100 proteins in autoinflammation: putative role in pathogenesis and usefulness as biomarkers. Clin Immunol 147:229–241.

    CAS  Article  Google Scholar 

  16. 16.

    Kessel C et al (2017) Pro-inflammatory cytokine environments can drive IL-17 over-expression by gammadeltaT cells in systemic juvenile idiopathic arthritis. Arthritis Rheumatol.

    CAS  Article  Google Scholar 

  17. 17.

    Kessel C, Fuehner S, Zell J, Zimmermann B, Drewianka S, Brockmeyer S, et al. (2018) Calcium and zinc tune autoinflammatory toll-like receptor 4 signaling by S100A12. J Allergy Clin Immunol.

  18. 18.

    Kolly L et al (2013) Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1beta production. J Allergy Clin Immunol 131:1635–1643.

    CAS  Article  Google Scholar 

  19. 19.

    Kuemmerle-Deschner JB et al (2011) Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum 63:840–849.

    Article  Google Scholar 

  20. 20.

    Kumar RK, Yang Z, Bilson S, Thliveris S, Cooke BE, Geczy CL (2001) Dimeric S100A8 in human neutrophils is diminished after phagocytosis. J Leukocyte Biol 70:59–64

    CAS  PubMed  Google Scholar 

  21. 21.

    Lachmann HJ et al (2009) In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes. J Exp Med 206:1029–1036.

    CAS  Article  Google Scholar 

  22. 22.

    Lieber M, Kallinich T, Lohse P, Klotsche J, Holzinger D, Foell D, Wittkowski H (2015) Increased serum concentrations of neutrophil-derived protein S100A12 in heterozygous carriers of MEFV mutations. Clin Exp Rheumatol 33:S113–S116

    PubMed  Google Scholar 

  23. 23.

    Lim SY et al (2008) S-nitrosylated S100A8: novel anti-inflammatory properties. J Immunol 181:5627–5636

    CAS  Article  Google Scholar 

  24. 24.

    Loser K et al (2010) The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med 16:713–717.

    CAS  Article  Google Scholar 

  25. 25.

    Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM, Aksentijevich I, Kastner DL (2001) The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood 98:851–859

    CAS  Article  Google Scholar 

  26. 26.

    Moroz OV et al (2009) Both Ca2+ and Zn2+ are essential for S100A12 protein oligomerization and function. BMC Biochem 10:11.

    Article  Google Scholar 

  27. 27.

    Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C (1997) Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem 272:9496–9502

    CAS  Article  Google Scholar 

  28. 28.

    Reinhardt K et al (2014) Monocyte-induced development of Th17 cells and the release of S100 proteins are involved in the pathogenesis of graft-versus-host disease. J Immunol 193:3355–3365.

    CAS  Article  Google Scholar 

  29. 29.

    Roth J, Burwinkel F, van den Bos C, Goebeler M, Vollmer E, Sorg C (1993) MRP8 and MRP14, S-100-like proteins associated with myeloid differentiation, are translocated to plasma membrane and intermediate filaments in a calcium-dependent manner. Blood 82:1875–1883

    CAS  PubMed  Google Scholar 

  30. 30.

    Rubartelli A, Cozzolino F, Talio M, Sitia R (1990) A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence. EMBO J 9:1503–1510

    CAS  Article  Google Scholar 

  31. 31.

    Steinckwich N, Schenten V, Melchior C, Brechard S, Tschirhart EJ (2011) An essential role of STIM1, Orai1, and S100A8-A9 proteins for Ca2+ signaling and FcgammaR-mediated phagosomal oxidative activity. J Immunol 186:2182–2191.

    CAS  Article  Google Scholar 

  32. 32.

    Vogl T et al (2004) MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood 104:4260–4268.

    CAS  Article  Google Scholar 

  33. 33.

    Vogl T et al (1999) S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14. J Biol Chem 274:25291–25296

    CAS  Article  Google Scholar 

  34. 34.

    Wittkowski H et al (2008) S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown origin. Arthritis Rheum 58:3924–3931.

    CAS  Article  Google Scholar 

  35. 35.

    Wittkowski H et al (2011) MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes. Ann Rheum Dis 70:2075–2081.

    CAS  Article  Google Scholar 

Download references


DF and CK are funded by INSAID (DFG funding FO 354/11-1).

Author information




DH, CK, and DF contributed to the mini-review drafting and finalizing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Dirk Holzinger.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, 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.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Holzinger, D., Foell, D. & Kessel, C. The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases. Mol Cell Pediatr 5, 7 (2018).

Download citation


  • S100 proteins
  • Autoinflammation
  • DAMP
  • Biomarker
  • Fever of unknown origin
  • Diagnosis
  • Monitoring
  • TLR agonist
  • Calgranulins