OP002 The GCN2/eIF2α/ATF4 signaling pathway is necessary for autophagy response to infection with Crohn's disease-associated adherent-invasive Escherichia coli

Abstract

Background: Results from animal models and human studies have highlighted a role for the IL23/IL17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL23-driven inflammation has been primarily linked to Th17 cells. Work from our lab has identified a novel population of IL23-responsive innate lymphoid cells (ILC) that drive colitis in innate murine models through IL17 and IFN-gamma production. Furthermore, IL22-producing ILC were shown to sustain the development of bacteria driven colitis-associated cancer in mice. However, the relevance of ILC in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL23-induced cytokines and IL23-responsive ILC in the human intestine in health and in IBD. Methods: Lamina propria mononuclear cells were isolated from surgical specimens and biopsies from controls and patients with IBD, using mechanical and enzymatic digestion protocols. Intestinal and systemic immune responses were analysed by surface and intracellular FACS staining. CD56 and CD56+ ILC were sorted by FACS and cultured overnight in presence or absence of IL23. RNA gene expression was analysed by qPCR. Results: We identified CD127+ ILC populations in the human intestine and peripheral blood and observed a significant increase in the frequency of CD56 CD127+ ILC in the inflamed ileum and colon of patients with Crohn’s disease. IL17A and IL17F gene expression was restricted to CD56 ILC, whereas IL23 induced IL22 and IL26 in the CD56+ ILC compartment. Interestingly we observed an increased CD127+ ILC frequency in the colon of patients with IBD and primary sclerosing cholangitis (PSC), where increased frequencies of IL22+ CD3+ T cells were also present. Conclusions: These results indicate that IL23-responsive ILC are present in the human intestine and that intestinal inflammation is associated with the accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. IL22 is involved in tissue repair and induces proliferation and survival of epithelial cells. Uncontrolled IL22mediated T-cell and ILC-responses may contribute to the increased risk of colorectal cancer observed in patients with IBD and PSC. ILC may participate in intestinal inflammation through cytokine production, lymphocyte recruitment, or organization of the inflammatory tissue and represent a novel tissue-specific target for subtypes of IBD. OP002 The GCN2/eIF2a/ATF4 signaling pathway is necessary for autophagy response to infection with Crohn’s disease-associated adherent-invasive Escherichia coli H. Nguyen1 *, J. Carriere1, G. Dalmasso1, A.-C. Maurin2, A. Bruhat2, A. Darfeuille-Michaud1. 1University of Auvergne, UMR 1071/Inserm, Clermont-Ferrand, France, 2INRA, Human nutrition unit (UNH), Theix, France