IL17 signaling in intestinal epithelial cells regulates host-microbiota interaction controlling neuroinflammation in atherosclerosis 3026

Abstract Description While microbiota regulates immunity, and altered microbiota composition was linked to atherosclerosis, the role of cytokine signaling in intestinal epithelial cells (IEC) controlling host-microbiota interactions in atherosclerosis remains unknown. Here we found that IL17RC deletion in IEC enhanced atherosclerosis in Western diet (WD) fed Ldlr-/-Il17rcDIEC mice that was accompanied by reduced mucus and junction proteins and enhanced gut permeability. RNAseq analysis revealed heightened inflammation and altered luminal and adhesive microbiota composition in small intestines of Ldlr-/-Il17rcDIEC mice with atherosclerosis. Single cell RNA seq of immune cells showed accumulation of IL17A + gdT cells in aortas of Ldlr-/-Il17rcDIEC mice. Furthermore, atherosclerosis in Ldlr-/-Il17rcDIEC mice was accompanied by neuronal expansion and activation as determined by RNA seq and microscopy, while chemical denervation suppressed the disease. The expansion of Th1+ sympathetic neurons is aortas of Ldlr-/-Il17rcDIEC mice was microbiota dependent as co-housing enhanced the disease in IL17RC sufficient mice, while microbiota depletion suppressed it, along with neuronal and inflammatory signatures in aortas. Overall, our work uncovers novel role of IL17RC signaling in atherosclerosis and shows that intestinal IL17RC controls the disease by keeping in check intestinal barrier and microbiota that in turn regulates IL17A + gdT cells and neuroinflammation in aorta. Funding Sources Supported by NIH/NHLBI 1R01HL173975-01 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)