The complex networks, interactions and reactions of immune cells give rise to a cellular ecosystem consisting of numerous cell types accompanied by the genetic diversity of antigen receptors (13). involvement in atherosclerotic plaque evolution are becoming known. In this review, we examine the critical immune responses involved in atherosclerotic plaque evolution, in particular, looking at atherosclerosis from the perspective of evolutionary immunobiology. A comprehensive understanding of the interplay between plaque evolution and plaque immunity provides clues for strategically combating GR 103691 atherosclerosis. Keywords:atherosclerosis, plaque evolution, immune response, immune cell heterogeneity, inflammatory microenvironment, immunotherapy == 1. Introduction == Atherosclerotic cardiovascular disease (ACD) is a prominent global cause of mortality (1). Atherosclerosis is a slow process, characterized by multifocal structural changes in the vascular wall of large and medium- sized arteries, which result in the development of atherosclerotic plaques (2). Atherosclerotic plaques are the pathophysiological basis of almost all arterial vascular diseases. Advanced plaques may rupture, triggering thrombosis that blocks arteries and disrupts blood flow, leading to an array of life-threatening clinical outcomes called major adverse cardiovascular events (MACEs) (3). Past epidemiologic studies have revealed many risk factors for atherosclerosis, among which traditional risk factors include dyslipidemia, hypertension, hyperhomocysteinemia, hyperfibrinogenemia, diabetes mellitus, smoking, obesity, and genetic predisposition. In recent years, nontraditional drivers such as sleep disorders, lack of exercise, air pollution, environmental stress, as well as inflammation and clonal hematopoiesis associated with the immune system have also received attention (3,4). The evolution of atherosclerotic plaques can be broadly categorized into three stages: initiation, progression and complications. It has been shown that fatty streaks are the initial marker of atherosclerosis, which develops in four actions: low-density lipoprotein (LDL) cholesterol uptake, endothelial cell (EC) activation, leukocyte activation and foam GR 103691 cell formation (5). During the development of fibrous plaques, atherosclerotic plaques experience a shift from fatty streaks to intimal growth, and this step is usually marked by the formation of a lipid-rich necrotic core covered by a fibrous cap. The fibrous cap is composed of vascular smooth muscle cells (VSMCs) which migrate to the side of the arterial lumen and VSMC-derived extracellular matrix (ECM). The atherosclerotic plaques can rupture at the point where the fibrous cap is usually thinnest exposing the material inside to blood tissue triggering thrombosis. If the lumen is usually blocked, the narrowing of the diseased artery can also lead to other complications such as heart and brain infarction (6,7). Among GR 103691 the many factors that influence the evolution of atherosclerotic plaques, the immune system plays a significant role. During the formation and development of atherosclerotic plaques, the local microenvironment undergoes a series of complex changes, accompanied by the infiltration of multiple immune cells. Evidence suggests that circulating monocytes and resident vascular macrophages are the earliest immune cells recruited into early atherosclerotic plaques GR 103691 (8). Following this, various immune cells such as neutrophils, natural killer (NK) cells, DCs, T cells and B cells gradually infiltrate the plaque and perform their regulatory functions. Subpopulations of leukocytes in the arterial wall are heterogeneous they play a pro-inflammatory or regulatory role in atherosclerotic plaque formation. Most patients with atherosclerosis are immunocompetent individuals (9). The key takeaway about the impact of immune function is usually that it is complex, and immunomodulation can positively or negatively affect the evolution of atherosclerotic plaques. The molecular signals that regulate leukocyte recruitment to atherosclerotic lesion sites are complex, and chemokines and their receptors play a key role and have received much attention in the study of atherosclerosis. Chemokines are a class of small, secreted cytokines with chemotactic properties. Depending on the location of their cysteine residues, they can be divided into four subclasses: C, CC, CXC, and CX3C. They act mainly by GR 103691 binding to specific G-protein-coupled chemokine receptors (10). In atherosclerotic lesions, chemokines and many of their receptors are expressed in endothelial cells, leukocytes, and easy muscle cells, with highest expression especially in regions near the necrotic core. They are widely involved in all stages of atherosclerosis by promoting immune cell adhesion, migration, infiltration, CD350 differentiation, and homing to the lesion site (11). With the advent and advancement of various experimental techniques, we have gained an understanding of the mechanisms involving the immune system in plaque evolution. Here, we view atherosclerotic plaque lesions from the perspective of evolutionary immunobiology, specifically reviewing the immunologic aspects of plaque evolution, including the immune responses involved, the effects of immune cell heterogeneity, and plaque dynamics in the inflammatory microenvironment. The goal.