P-317 The Role of ILC2s Activated by Microbiota-induced IL-33 in the Pathogenesis of Crohn's-like Ileitis

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Emerging evidence points to the critical role of the innate immune system in the pathogenesis of inflammatory bowel disease (IBD). Innate lymphoid cells (ILCs) are a recently described immune cell population that is commonly found, but not limited to, mucosal surfaces, that interacts directly with both hematopoietic and non-hematopoietic cells to orchestrate immunity, inflammation and homeostasis in multiple tissues throughout the body, including the gastrointestinal tract. The subset ILC2 can be activated by the cytokine interleukin (IL)-33, and secretes type 2 cytokines, such as IL-5 and IL-13, that promote inflammatory cell infiltration and epithelial barrier damage during IBD. A significant association and an increase in expression of IL-33 and its receptor, ST2 have been detected in intestinal epithelial cells and inflammatory infiltrates in IBD patients, and this increase is associated with disease severity in the Th1/Th2 SAMP1/YitFc (SAMP) model of chronic ileitis. While its precise role in acute (primarily chemically-induced) models of colitis is controversial, indicating both pathogenic and protective functions, we recently showed that blockade of IL-33 signaling ameliorates chronic inflammation in SAMP mice, and that the gut microbiome is essential for IL-33 expression in these mice. Though the contributions of the subsets ILC1 and ILC3 in IBD have been somewhat delineated, a definitive role for ILC2 in chronic intestinal inflammation has yet to be established.


Mesenteric lymph nodes (MLNs) and lamina propria (LP) from wildtype SAMP, SAMPxRAG2−/−, SAMPxNOD2−/−, and control AKR mice were processed into single cell suspension and analyzed for ILC2s via flow cytometry. Ileal tissue from SAMP, SAMPxRAG2−/−, and AKR mice were processed for histological analyses and evaluated for inflammatory scores. Expression of Th2 cytokines in ileal tissues of SAMP and SAMPxRAG2−/− mice were evaluated by quantitative real time PCR.


Since IL-33 is also known to induce the expansion and cytokine production of ILC2s, the aim of this study was to determine the contribution of IL-33-responsive ILC2s to chronic intestinal inflammation in SAMP mice. Our results showed a dramatic increase in frequency and absolute numbers of ILC2s within the draining MLNs (P < 0.05 and P < 0.05, respectively) and LP (P < 0.05 and P < 0.05, respectively) of SAMP versus AKR mice, which also demonstrated increased MLN-derived IL-5-expressing ILC2s (P < 0.05). In fact, ST2+ ILC2s drastically expanded after exogenous IL-33 administration versus vehicle-treated controls (P < 0.0001). At the peak of ileitis at 10 weeks, it was determined that the absence of T cells in SAMPxRAG2−/− mice did not influence ileal inflammatory scores and Th2 cytokine gene expression. Additionally, a significant percentage of ILCs in SAMPxRAG2−/− mice are comprised of ILC2s, indicating that ileal inflammation at its peak may be contributed mostly by ILC2s. Interestingly, SAMP lacking the bacterial sensor for muramyl dipeptide (SAMPxNOD2−/−), showed a decrease in MLN-derived ILC2s versus WT-SAMP, suggesting that components of the gut microbiome may be necessary for ILC development and expansion during chronic gut inflammation.


Overall, our data reveals that the IL-33/ST2 axis may mechanistically contribute to chronic intestinal inflammation, such as that observed in IBD through the development of pathogenic ST2+ ILC2s.

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