PRJNA390408
The role of NIK in inflammatory bowel disease, Jun 13 2017
High basal inflammatory tone of the intestine is required for protection against pathogens and commensal microflora. The same protective pathways if activated chronically could lead to injury. Identifying homeostatic inflammatory pathways is essential in delineating mechanisms that are important in inflammatory bowel disease (IBD). Unlike the classical NF?B pathway, the role of the non-canonical NF?B signaling mediated by NF?B inducing kinase (NIK) in the pathogenesis of inflammatory diseases are not known. In the intestine, NIK signaling is highly active in secondary lymphoid follicles. Using conditional knockout mice, we demonstrate that epithelial NIK signaling (but not hematopoietic) maintain immune homeostasis by regulating the differentiation and maintenance of M-cells. Mechanistically, we show this response is a critical molecular link between epithelial sensing of luminal antigens and local and systemic IL-17A response. However, intestinal NIK signaling is chronically active in mouse models of colitis and IBD patients. Constitutive NIK signaling led to a robust susceptibility to inflammatory injury through ectopic M-cell differentiation and a chronic increase in IL-17A. This work provides the first mechanistic characterization of the non-canonical NF?B in intestinal inflammation, and demonstrates a critical homeostatic function of NIK in intestinal epithelial cells.