Artery tertiary lymphoid organs, neuro-immune interaction and their mediators in atherosclerosis

Atherosclerosis is a chronic inflammatory disease characterized by the irreversible remodeling of the arterial wall; severe atherosclerotic lesions may lead to life-threatening consequences such as major ischemic events (i.e., myocardial infarction (MI) and stroke) and abdominal aortic aneurysm (AAA) rupture. The severity of the lesions is determined by multiple risk factors that cause systemic and cellular metabolic changes, oxidative damage, cell senescence, and immune activation involving both leukocytes and vascular cells. In advanced stages, macrophage infiltration, alterations of the load-bearing collagenous matrix, and the presence of microcalcifications are the main drivers of plaque vulnerability. Over the last decade, the presence of artery tertiary lymphoid organs (ATLOs) has been established. These structures form during progressive atherosclerosis in the adventitia of large arteries and represent highly organized niches composed of T and B lymphocytes and innate immune cells. More recently, the presence of nerve fibers and the contribution of both the central (CNS) and peripheral (PeriphNS) nervous systems, through the action of sympathetic, parasympathetic, and somatosensory pathways regulating ATLO composition have been demonstrated. However, their role in atherosclerosis progression remains debated. This review explores the architecture of ATLOs and their neuroimmune interactions with the spleen, as a central neuroimmune organ, in atherosclerosis progression, with a particular focus on carotid stenosis and AAA. Furthermore, it highlights the neuronal mediators that could act as biomarkers of plaque instability and promising pharmacological targets. Finally, while still in the preclinical phase, it explores future prospects for integrating neuroimmune-based therapies into current clinical management of atherosclerosis.