Myeloid cell-intrinsic TAX1BP1 restrains spontaneous heart valve inflammation 2259602

Abstract

Abstract Introduction Tax1 binding protein 1 (TAX1BP1) is a selective autophagy receptor that inhibits activation of tumor necrosis factor (TNF)- and lipopolysaccharide (LPS)-induced NF-kB activation to suppress inflammation. TAX1BP1 has recently been shown to promote cell survival by degrading the kinase RIPK1 to inhibit tumor necrosis factor receptor 1 (TNFR1)-mediated necroptosis. However, the physiological roles and tissue specific functions of TAX1BP1 in the regulation of cell death and inflammation are poorly understood. Methods In this study, we utilized the Cre-loxP system to generate TAX1BP1 conditional knockout mice crossed with LysM-Cre mice for a myeloid cell-specific knockout (Tax1bp1fl/fl LysMCre mice). These mice were necropsied for pathological analysis. The mice were challenged with a low dose (2.5 mg/kg) of LPS to determine their susceptibility to inflammatory stimuli. Bone marrow-derived macrophages (BMDMs) and thioglycollate-elicited peritoneal macrophages (PMs) were also generated from Tax1bp1fl/fl LysMCre mice for in vitro studies. Results Tax1bp1fl/fl LysMCre mice develop splenomegaly and spontaneous heart valve inflammation and necrosis. They also exhibit increased pro-inflammatory cytokine production and sepsis upon intraperitoneal administration of a low dose of LPS. BMDMs and PMs from Tax1bp1fl/fl LysMCre BMDMs and PMs undergo spontaneous lytic cell death that can be rescued with a kinase inactive RIPK1 D138N allele. Conclusion These findings highlight TAX1BP1 as a critical regulator of myeloid cell homeostasis by suppressing NF-kB signaling and inflammation while promoting cell survival. Additionally, the severe cardiac valvulitis that spontaneously develops in Tax1bp1fl/fl LysMCre mice indicates that TAX1BP1 expression in cardiac resident macrophages is critical for the homeostasis of these cells and inhibition of inflammation and necrosis in heart valves. Funding Source NIH/NIAID R01AI162815 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)