IL-17RC signaling in intestinal epithelial cells protects against atherosclerosis by maintaining barrier function and microbiota homeostasis, while loss of this signaling triggers a pathogenic cascade in which altered microbiota drives accumulation of IL-17A-producing γδ T cells in atherosclerotic aortas that stimulate sympathetic neuronal expansion and activation through cell-autonomous IL-17 signaling in neurons, ultimately promoting inflammatory macrophage activation and atherosclerosis progression.

While dysbiosis and inflammation were previously implicated in cardiovascular diseases, the circuits of how microbiota drives distant perivascular innervation, neuroinflammation and atherosclerosis remains unknown. Here, we report that IL-17RC signaling in intestine protects from atherosclerosis controlling intestinal barrier and microbiota, and loss of IL-17RC in intestinal epithelial cells alters microbiota, enhances perivascular innervation and aortic inflammation, augmenting the disease. Neuronal outgrowth is functionally dependent on microbiota and is essential for neuroinflammation and augmentation of atherosclerosis as chemical denervation reduces inflammation, macrophage activation and disease progression. Microbiota-dependent IL-17A producing γδ T cells accumulate in aorta to promote neuronal outgrowth and activation that can be reversed by γδ T cell blockade. Perivascular neuron activation is further dependent on cell autonomous IL-17 signaling as IL-17RC ablation in sympathetic neurons protected mice from microbiota-driven atherosclerosis. Together, our data illuminate how intestinal cytokine signaling distantly restrains neuroimmune interactions in aorta and uncovers a novel link between IL-17 signaling, microbiota, perivascular innervation and neuroimmune pro-inflammatory crosstalk instrumental for atherosclerosis progression.

IL-17RC signaling regulates intestinal dysbiosis and perivascular neuronal outgrowth that modulates inflammation in atherosclerosis.