TAK1 Inhibition Induces a Novel Inflammatory Cell Death Pathway 2749

Description TAK1 is a key signaling molecule that mediates inflammatory responses by activating the transcription factor NF-κB and MAPK pathways. TAK1 is activated by pathogen infection through pattern recognition receptors and proinflammatory cytokines. Some pathogens are known to inhibit TAK1 to evade host inflammatory responses, which benefits the pathogens. However, our lab has identified that TAK1 inhibition elicits CASP8-dependent apoptosis and pyroptosis, and RIPK3-dependent necroptosis to alternatively induce inflammation to block these pathogens. Interestingly, we further found that CASP8 and RIPK3 pathways are partially dispensable in inducing cell death upon TAK1 inhibition. It raises the possibility that a previously unknown CASP8 and RIPK3-independent cell death occurs. I aim to elucidate the mechanisms of this pathway by generating and characterizing inducible Tak1, CASP8, and Ripk3-deficient mice and tissue culture. Our results show that TAK1 inhibition in the absence of CASP8 and RIPK3 doesn’t activate CASP3 or the pore-forming protein GSDMD, suggesting that this cell death is neither apoptosis nor pyroptosis. In vivo, Tak1 gene deletion in CASP8 and Ripk3-deficient mice led to increased inflammatory cytokines and chemokines, accompanied by gradual weight loss, which may resemble human inflammatory diseases. Unraveling this novel cell death mechanism will enhance our understanding of cell death pathways and add to identify therapeutic targets for inflammatory diseases. Funding Sources Supported by NIH R35GM139601 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)