- Mini review
- Open Access
The role of hypoxia in intestinal inflammation
© Shah. 2016
Received: 30 November 2015
Accepted: 5 January 2016
Published: 26 January 2016
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestine. IBD is a multifactorial disorder, and IBD-associated genes are critical in innate immune response, inflammatory response, autophagy, and epithelial barrier integrity. Moreover, epithelial oxygen tension plays a critical role in intestinal inflammation and resolution in IBD. The intestines have a dynamic and rapid fluctuation in cellular oxygen tension, which is dysregulated in IBD. Intestinal epithelial cells have a steep oxygen gradient where the tips of the villi are hypoxic and the oxygenation increases at the base of the villi. IBD results in heightened hypoxia throughout the mucosa. Hypoxia signals through a well-conserved family of transcription factors, where hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. In inflamed mucosa, HIF-1α increases barrier protective genes, elicits protective innate immune responses, and activates an antimicrobial response through the increase in β-defensins. HIF-2α is essential in maintaining an epithelial-elicited inflammatory response and the regenerative and proliferative capacity of the intestine following an acute injury. HIF-1α activation in colitis leads to a protective response, whereas chronic activation of HIF-2α increases the pro-inflammatory response, intestinal injury, and cancer. In this mini-review, we detail the role of HIF-1α and HIF-2α in intestinal inflammation and injury and therapeutic implications of targeting HIF signaling in IBD.
The intestine is a highly regenerative tissue, which completely renews every 5 to 6 days. The intestinal epithelial cells are critical for digestion, secretion of hormones and mucin, and absorption of nutrients. The epithelial cells are under control by an exquisite signaling cascade (Notch, BMP, Wnt/β-catenin) that maintains proliferation and differentiation of epithelial progenitors and the self-renewal capacity of intestinal epithelial stem cells. In addition, cellular oxygen dynamics are critical in maintaining intestinal homeostasis. The intricate oxygen gradient in the intestine is set up by the rapid propagation of the enteric microbiota just after birth. The microbiota composition of newborns suggests that aerobic and facultative anaerobic bacteria consume luminal oxygen, which allows the growth of obligate anaerobes and establishes an anoxic lumen . The anoxic lumen in part establishes the oxygen gradient of the intestinal epithelium, as cells directly adjacent to the lumen are hypoxic relative to the cells that are close to the base of the crypts . Moreover, microbiota-derived short-chain fatty acids regulate oxygen consumption in intestinal epithelial cells . Dysregulation of oxygen gradients is observed in inflammatory bowel disease (IBD). IBD is divided into two major subgroups: ulcerative colitis (UC) and Crohn’s disease (CD). The precise etiology of IBD is unknown. However, oxygen signaling plays an important function in the inflammatory and injury response.
Oxygen sensing and signaling in the intestine
Hypoxia and IBD
Using staining techniques to visualize hypoxic foci, a robust increase in hypoxia is observed in mouse models of colitis . Physiological hypoxia as mentioned above is localized to epithelial cells adjacent to the lumen. In colitis, hypoxic staining is observed throughout the mucosa. The precise mechanism for the increase in hypoxia is not clear, but it is likely due to several factors. Inflammation leads to enhanced oxygen consumption of intestinal epithelial cells. Inflammation increases local vasculitis and thus decreasing the oxygen availability to inflamed areas . Recently, it was shown that transmigrating neutrophils can consume local oxygen, thereby enhancing hypoxia in colitis . In addition to hypoxic staining in mouse models, HIF-1α and HIF-2α are highly increased in epithelial cells in UC and CD patients . Currently, the expression and function of HIF-3α have not been thoroughly assessed.
HIF-1α and HIF-2α targets in IBD
Currently, the pan-PHD inhibitors dimethyloxaloylglycine, FG-4497, and TRC160334 are protective in mouse models of colitis [14, 15, 22]. However, HIF-2α may increase the inflammatory response, and therefore, optimal HIF-based therapies would be pharmacological agents that can specifically increase HIF-1α. AKB-4924 is a PHD inhibitor that results in modest activation of HIF-2α but robustly activates HIF-1α . AKB-4924 increases the antimicrobial response and protective innate immune response. AKB-4924 treatment improves the intestinal barrier integrity and reduces the pro-inflammatory response. The beneficial effects of AKB-4924 were due to intestinal HIF-1α, as disruption of HIF-1α attenuated the protective role . Moreover, HIF-2α inhibitors have been recently identified. HIF-2α (but not HIF-1α) contains ligand-binding cavity, although endogenous substrates have not been identified . This cavity has been targeted for drug development, and several promising highly specific small-molecule inhibitors are identified . Currently, these drugs have not been assessed in mouse models of colitis, but the data suggest that disruption of intestinal epithelial HIF-2α decreases the inflammatory response in colitis .
HIF-1α and HIF-2α play an essential role in IBD. Understanding the temporal regulation of HIF-1α and HIF-2α will be key to design novel and effective HIF-based therapies for IBD. It is likely that both responses are critical in the initiation and resolution of intestinal inflammation. HIF-1α increases the barrier integrity and antimicrobial response, whereas HIF-2α activates pro-inflammatory mediators to elicit an immune response and stimulates epithelial proliferation to promote regeneration. However, more work is needed to understand the dynamic regulation of HIF-1α and HIF-2α in models of chronic colitis.
This work was supported by NIH grants: CA148828 and DK095201, to YMS.
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
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