TNFAIP3 DRIVES COLITIS THROUGH DEATH CELL AND TNFα PRODUCTION

Abstract IBD is characterized by inflammation involving a complex interplay between innate and adaptive immunity, non-immune cells, intestinal microbes. To understand the contributions of immunity to during colitis we have developed chronic model immune-mediated wherein RAG1-/- mice are crossed with expressing TNFAIP3 in epithelial cells (villin-TNFAIP3 mice). These villin-TNFAIP3 x (TRAG) develop early onset, 100% penetrant, driven gut inflammatory signals that lead this model, TRAG TNFα-/- (FRAG mice) compared severity vs. FRAG mice. In addition, TNFα-producing myeloid populations from lamina propria Finally, assessed expression localization proteins involved cell death pathways, unravel mechanisms driving innate-immune mediated colitis. Our results show that, mice, significantly increased numbers leukocytes, including neutrophils, monocytes, macrophages, dendritic lymphoid cells. lacking TNFα had lower all these leukocyte subsets. Consistent this, histological scores, Inflammatory neutrophils were found be main sources production, while production was null or minimal natural killer ILC1, ILC3 IC2. Macrophages monocytes iNOS, whereas macrophages notably marked Arginase1 expression. Localization active caspase3, phosphor-MLKL TUNEL positive indicated extensive crypt markedly suppressed Together our drives immune colitis, potentially through induction IEC necroptosis. well known as negative regulator receptor-mediated NFκB MAPK activation therefore attempts increase considered promising avenues for prevention inflammation. The present study, indicating TNFα-induced highlights potential tissue-specific roles should paradigm target