Sympathetic neurons exacerbate atherosclerosis by modulating macrophage function via the NPY/Y1R axis

Neuroimmune crosstalk is increasingly recognized in atherosclerosis, yet the contribution of the sympathetic neuron-macrophage axis remains unclear. We investigated whether and how sympathetic innervation promotes atherosclerosis through modulation of macrophage phenotype and function.

ApoE^-/- mice with or without sympathetic denervation were fed a high-fat diet to examine the role of sympathetic innervation in atherogenesis. Plaque burden and stability, inflammatory cytokine expression, macrophage phenotype, and related signaling pathways were analyzed by histopathological staining, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot. A macrophage-sympathetic neuron coculture system was used to explore neuron-macrophage interactions in vitro. The role of neuropeptide Y receptor Y1 (Y1R) was evaluated using the selective antagonist BIBO3304.

Single-cell RNA sequencing and histopathological analyses supported a role for sympathetic neurons in atherosclerosis through regulation of macrophage function. Sympathetic denervation reduced lesion burden and improved plaque stability in ApoE^-/- mice. In vitro, Y1R inhibition significantly attenuated proinflammatory cytokine expression in a macrophage-sympathetic neuron coculture system. In vivo, targeting Y1R with BIBO3304 reduced total atherosclerotic area and necrotic core size, decreased the proportion of proinflammatory macrophages, and enhanced plaque stability. Mechanistically, NPY/Y1R signaling promoted macrophage polarization toward a proinflammatory phenotype by activating the p38 and JNK pathways.

Sympathetic signaling accelerates atherosclerosis by driving proinflammatory macrophage polarization through the NPY/Y1R axis. Targeting sympathetic inputs or Y1R may offer a therapeutic approach for suppressing vascular inflammation and promoting plaque stabilization.