Artery Tertiary Lymphoid Organs Establish Biological Platforms to Connect Atherosclerotic Plaques to the Brain

The ability of the nervous system to sense cues from medium and large arteries is critical for maintaining vascular integrity and function. However, there is currently no evidence that atherosclerotic plaques of arteries other than arterioles are directly hard-wired by axons to transmit signals to the brain or that efferent axons from the brain gain access to plaques. Yet, studies in experimental mice have shown that the outer connective tissue coat of arteries, i.e. the adventitia, adopts sentinel functions to indirectly and faithfully connect plaques to the brain forming artery brain circuits (ABCs). This review focuses on the adventitia as a site that establishes powerful biological platforms in the form of highly innervated neuroimmune cardiovascular interfaces (NICIs) and shows that these interfaces impact atherosclerosis progression.

The discovery of several cardiovascular brain circuits over the last several years considerably expanded our understanding how neural circuits regulate artery and heart homeostasis and disease. These circuits release neurotransmitters to modify leukocyte trafficking, affect endothelial cells, control vascular smooth muscle cells (VSMCs) behavior, and regulate local inflammation. Moreover, vascular inflammation in turn reorganizes neural innervation in the adventitia suggesting that tripartite communication networks between the cardiovascular, the nervous and the immune systems impact disease progression. In atherosclerosis, the formation of artery tertiary lymphoid organs (ATLOs) represents a specific form of NICIs adjacent to atherosclerotic plaques. The ATLO-associated NICIs act as hubs to connect plaques to the brain via multisynaptic projections and receive signals from the brain to convey to the arteries. These insights reveal a previously underappreciated level of integration between neural, immune and vascular networks in the pathogenesis of cardiovascular diseases. In this review, we consider recent advances in neuroimmune and neurovascular interactions in atherosclerosis, with a particular focus on the mechanisms by which these pathways contribute to disease progression.