Abstract Body (Do not enter title and authors here): Atherosclerosis is a chronic inflammatory disease involving the entire arterial wall including the adventitia, now recognized as an active compartment in immune and vascular control. We previously showed that chronic adventitial inflammation in ApoE^-/- mice leads to artery tertiary lymphoid organs (ATLOs) formation and establishes a neural artery-brain circuit. Afferent signals activate a reflex sympathetic drive fostering plaque progression. A surgical denervation via celiac ganglionectomy (CGX) led to a decrease in plaque size and the collapse of ATLOs, suggesting a causal role of the sympathetic nervous system in controlling vascular vulnerability during pathology. This work aims to elucidate the underlying mechanisms.
To this aim ApoE^-/- mice were subjected to CGX during early stages of atherosclerosis and monitored over time for the following 8 months. Celiac sympathectomy promoted a local immune response in the aorta by significantly expanding macrophages. To characterize the phenotype of the ensuing arterial immune response, we analyzed the distribution of LYVE1⁺ and CD68⁺ macrophages, representing the adaptive and maladaptive response, respectively. LYVE1⁺ macrophages, which normally line along the interface between media and adventitia and in the outermost adventitial portion, are progressively lost during atherosclerosis, concomitantly to adventitial disorganization. Whereas CD68⁺ macrophages increase in number in plaques, indicating marked inflammatory infiltration. Notably, CGX induced a partial recovery of localization and number of LYVE1⁺ macrophages at the interface between media and adventitia layer, a phenotype that associated with a reduction in plaque expansion and vulnerability, as observed both at histological and in vivo ultrasonography. Conversely, CD68⁺ macrophages were reduced in plaques of ApoE^-/- mice subjected to celiac sympathectomy.
Recently, it has been shown that macrophages with atheroprotective functions express Neuropilin-1 (NRP1), and we found that a neural circuit modulates a subpopulation of NRP1⁺LYVE1⁺ macrophages in the heart. Hence, we tested whether CGX could modulate atherosclerosis by influencing this macrophage population, finding that NRP1⁺LYVE1⁺ significantly expanded in ApoE^-/- mice subjected to surgical celiac denervation. Taken together, our results suggest that sympathetic nervous system negatively controls the atheroprotective innate immune response, contributing to plaque progression and vulnerability.