Abstract 2142: IL-17 Signaling In Intestinal Epithelial Cells Regulates Microbiota, Metabolism And Neuroinflammation In Atherosclerosis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 44; no. Suppl_1
• Main Authors: Mazitova, Aleksandra, Marquez Sanchez, Ana C, Terrell, Meghan, Rodrigues, Richard, Trinchieri, Giorgio, Dzutsev, Amiran, Kossenkov, Andrew, Grivennikov, Sergei, Koltsova, Ekaterina
• Format: Journal Article
• Language: English
• Published: 01.05.2024
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.44.suppl_1.2142

Abstract only Microbiota plays a crucial role in regulating immunity and has been suggested to contribute to atherosclerosis, the precise role of cytokine signaling in intestinal epithelial cells (IEC) in controlling microbiota, inflammation, and vascular disease is poorly understood. Here we investigate the role of IL-17RC signaling in intestinal epithelial cells (IEC) using newly generated Ldlr -/- Il17rc Δ IEC mice. We found that IEC-specific ablation of IL-17RC heightened intestinal inflammation, altered microbiota composition, and led to enhanced atherosclerosis development accompanied by accumulation of activated myeloid and T cells in aortas along with upregulation of genes reminiscent of neuroinflammatory signature. IL-17RC ablation in IEC reduced tight junction proteins contributing to enhanced gut permeability. RNAseq analysis of intestines revealed upregulation of multiple inflammatory pathways, including interferon and TLR signaling, while several metabolic pathways were downregulated in Ldlr -/- Il17rc Δ IEC mice; implying an important role of IL-17R signaling in the control of IEC metabolism, microbes and metabolites at the host-microbiota interface. Metagenomic sequencing revealed alteration of microbiota composition in Ldlr -/- Il17rc Δ IEC . Atherosclerosis development was microbiota dependent as co-housing enhanced the disease in control mice, while microbiota depletion significantly suppressed the disease.Our work uncovers novel protective role of IL-17 signaling in intestine which regulates the barrier, microbiota and metabolism leading to reduced neuroinflammation in atherosclerotic aorta.