Abstract 150: Cytokine Signaling In Intestinal Epithelial Cells As A Regulator Of Microbiota, Inflammation And Atherosclerosis

Abstract

While microbiota regulates immunity and was suggested to play a role in atherosclerosis, the specific role of cytokine signaling in intestinal epithelial cells (IEC) in control of microbiota, inflammation, and vascular disease remains unknown. We previously showed that IL-23 enforces intestinal barrier, controls pro-atherogenic bacteria, metabolites, and activation of myeloid cells, and protects from atherosclerosis. Here we investigate the role of IL-23-regulated IL-17 signaling in IEC using newly generated Ldlr -/- Il17rc fl/fl VillinCre + mice. We found that IEC-specific ablation of IL-17RC heightened subclinical intestinal inflammation, altered microbiota composition, and led to enhanced atherosclerosis development accompanied by accumulation of activated myeloid and T cells in aortas. Mechanistically, IL-17RC ablation in IEC reduced tight junction proteins as well as IgA transport to the lumen due to altered Pigr expression thereby contributing to the expansion of pro-atherogenic microbiota. RNAseq analysis revealed upregulation of multiple inflammatory pathways, including interferon and TLR signaling, while several metabolic pathways such as fatty acid oxidation and pyruvate pathways were downregulated in IL17RC IEC Ldlr -/- mice; implying an important role of IL-17R signaling in the control of IEC and microbial metabolism. Our work uncovers a novel protective role of IEC-specific IL-17 signaling in atherosclerosis and establishes a paradigm of cytokine-mediated regulation of barrier, microbiota, and metabolic pathways in cardiovascular diseases.