A9 IL37 SIGNALING THROUGH SIGIRR: A NOVEL APPROACH TO SUPPRESS INTESTINAL INFLAMMATION. (15th March 2019)

• Record Type: Journal Article
• Authors: Allaire, J M; Crowley, S M; Han, X; Poon, A; Vallance, B
• Is Part Of: Journal of the Canadian Association of Gastroenterology. Volume 2(2019)Supplement 2
• Page Start: 19
• Page End: 20
• Publication Date: 2019-03-15
• Subjects: Gastroenterology -- Periodicals; 616.33005
• DOI: 10.1093/jcag/gwz006.008
• Languages: English
• ISSNs: 2515-2084

Abstract

Abstract: Background: Inflammatory bowel diseases (IBD) are chronic inflammatory diseases affecting 1 in every 150 Canadians. In contrast to healthy individuals, IBD patients develop exaggerated inflammatory responses against their resident microbiota, at the level of the single layer of epithelial cells (IEC) lining the intestinal tract. Typically, the innate immune hypo-responsiveness of IEC prevents such maladaptive responses, in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. Its expression is reduced in IBD patients with active disease and in mouse models of colitis; its complete loss leads to necrotizing enterocolitis. Despite the importance of SIGIRR, its designation as an orphan receptor has limited its therapeutic potential to suppress inflammation. Recently however, IL-37, a newly recognized anti-inflammatory cytokine has been shown to signal through a receptor complex of SIGIRR and IL-18 receptor, to inhibit inflammatory signaling. Several studies have demonstrated that IL-37 inhibits innate signaling in cells expressing SIGIRR, thereby suppressing various forms of inflammation in mice. Aims: Study IL-37/SIGIRR effects on IEC innate signaling and infectious colitis. Methods: Using human IEC lines and human/mice derived intestinal organoids, we assessed the ability of IL37 to suppress innate signaling in IEC. IL37 transgenic mice and wildtype C57BL/6 mice injected with IL37 were used to define the in vivo effect of IL37 on gut inflammation during a bacterial ( Salmonella typhimurium ) driven colitis. Colitis severity was determined by macroscopic/histological scoring. qPCR, ELISA and Western blot measured cytokine, chemokine and antimicrobial peptide production; immunostaining quantified inflammatory cell recruitment. Results: We found that IL-37 suppress innate immune signalling (NFkB activation; production of IL-8, CCL20 chemokine) in human IEC stimulated by bacteria and cytokines. Using organoids derived from wildtype and Sigirr-/ - mice, we demonstrated that IL-37 suppress innate IEC responses ( Il-6, Cxcl1 and TNFα mRNA transcription; NFkB activation) in a SIGIRR dependent manner. Using S. typhimurium infection, we showed that the responsiveness of wildtype mice to IL37 treatment protected them from S. typhimurium infection by reducing luminal and intracellular pathogen burdens, intestinal tissue pathology and inflammation in concert with reducing cytokine and chemokine secretion by IEC. Conclusions: Taken together, our studies show that IL37 offers potential to suppress intestinal inflammation, through it signal on SIGIRR expressing IEC. Further investigations will determine the ability of IL37 to control microbial dysbiosis, as the therapeutic potential of IL37/SIGIRR to promote gut health by suppressing IEC inflammatory/antimicrobial responses. Funding Agencies: CAG, CCC, CIHRMSFHR