Artery Tertiary Lymphoid Organs Form Neuroimmune Cardiovascular Interfaces in Atherosclerosis

Abstract

Arterial walls of large- and intermediate-sized arteries consist of three layers, that is, the intima, the media, and the adventitia. Under physiological conditions, the intima mainly comprises endothelial cells and a few monocyte/macrophages and dendritic cells; the media consists of smooth muscle cells and elastic fibers; and the adventitia is a complex connective tissue with structures as diverse as scattered immune cells, small blood vessels, lymph vessels, and multiple components of the nervous system. This review focuses on a subtype of tertiary lymphoid structures termed artery tertiary lymphoid organs (ATLOs), which develop specifically in atherosclerotic arterial segments in the adventitia but not in normal arteries. ATLOs have been characterized in aging hyperlipidemic mice and later have been identified in various diseased segments of the arterial tree, including the carotid arteries, the coronary arteries, and the aorta in humans. The effects of ATLOs on atherosclerosis remain largely unknown. Indeed, ATLOs host pro-inflammatory and anti-inflammatory immune cell subtypes. Stage-III ATLOs contain activated B cell follicles in which germinal centers develop in apparent antigen-dependent B cell maturation cycles. Recent research supports the idea that ATLOs create neuroimmune cardiovascular interfaces (NICIs), which may serve as key hubs in which three tissues interact: the nervous system, the immune system, and the cardiovascular system. Recent evidence indicates that NICIs are capable of impacting disease progression. These interfaces connect atherosclerotic plaques to the immune system, produce disease-related autoantibodies, participate in the development of autoreactive T cells, and transmit signals from arteries to the brain and receive signals from the brain in hardwired polysynaptic axonal connections.