IL-17RC signaling connects intestinal microbiota and neuroimmune interactions in atherosclerosis

Here, we report that IL-17RC signaling in the 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 or chemogenetic inhibition reduces inflammation, macrophage activation and disease progression. Microbiota-dependent IL-17A producing gd T cells accumulate in the aorta to promote neuronal outgrowth and activation that can be reversed by gd 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.