POP3 regulates type I interferon and ameliorates intestinal inflammation - Summary: Inflammatory Bowel Disease (IBD) is a tremendous clinical problem, a life-long relapsing and remitting disease, which also increases the susceptibility for colorectal cancer and for which no medical cure exists. IBD is an inflammatory disease of the colon and the small intestine and includes Crohn’s disease (CD) and ulcerative colitis (UC) with still poorly understood underlying pathologies. Therefore, defining novel molecular mechanisms and pathways that protect or reduces the susceptibility of individuals from developing IBD is of high importance and significant for developing novel therapies. We originally discovered the PYRIN domain-only protein 3 (POP3), which is encoded in humans, but lacking from mice, as a specific inhibitor of dsDNA and DNA virus-induced AIM2 inflammasomes in macrophages. We now discovered that POP3 is expressed in a rare subset of human intestinal macrophages, but its expression is significantly downregulated in the colon of CD and UC patients. Conversely, mice with transgenic POP3 expression in macrophages, including intestinal macrophages, are significantly protected from intestinal inflammation in a mouse colitis model. Using genetic mapping, we identified that this effect is independent of its known role regulating the AIM2 inflammasome, but that the POP3 protection requires type I interferon. Our preliminary data further show that POP3 assembles into a novel nuclear signaling complex to promote a unique type I interferon signature to shape the intestinal immune cell and microbiome composition. The goal of this study is to determine the protective functional impact mediated by POP3 on intestinal homeostasis and inflammatory disease, to elucidate the underlying molecular mechanisms focusing on a novel POP3-containing nuclear protein complex that promotes type I interferon, and to identify and functionally characterize the POP3+ intestinal macrophage cell type that protects from IBD. We expect that our research will uncover novel protective molecular mechanisms, expand our knowledge on type I interferon signaling, and identifies novel targets for future therapies to positively impact the quality of life of IBD patients.
