Neuroimmune Cardiovascular Interfaces in Atherosclerosis

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Atherosclerosis is a chronic inflammatory disease of arteries caused by plaques in the inner layer of arteries. As plaques lack nerve fibers, the impact of neuronal control on atherosclerosis has not been considered before. Since the nervous system uses the adventitia, i.e. the outer connective tissue coat of arteries, as their major conduit to reach distant targets, we hypothesized that the nervous system may interact with diseased arteries via adventitial immune cells to sense and affect atherosclerosis. We identified and functionally delineated tripartite interactions between nerves, immune cells and diseased arteries in murine and human atherosclerosis using tissue clearing, multiplex immunostaining, intact aorta imaging, virus tracing, and single cell transcriptomics. We observed that atherosclerotic adventitia segments interact with the nervous system by stimulating axon growth adjacent to atherosclerotic plaques. Peripheral axon terminals directly interact with immune cells and form neuroimmune junctions. These interactions initiate a structural artery-brain circuit that directly wire diseased arteries with the brain to sense and affect atherosclerosis via dorsal root ganglia, sympathetic ganglia and the spinal cord. Multimodal imaging and electrophysiological nerve recordings revealed activation of central and peripheral components of artery-brain circuits in parallel to disease progression. When these interactions are disrupted by systemic or local sympathetic denervation in mice, plaque-associated immune cell aggregates in the adventitia destabilized, plaques shrunk and showed a more stable phenotype. These data provide a new disease paradigm to understand atherogenesis through multisystemic tissue interactions between the nervous system, the immune system and the cardiovascular system. In summary, our data demonstrated that neuroimmune cardiovascular interactions affect atherosclerosis progression. These studies suggest that neuroimmune cardiovascular interfaces represent new targets using pharmaceutical, surgical and bioelectronic modulations before the disease including becomes life-threatening.