Abstract
Atherosclerosis is a hardening and narrowing of arteries causing a reduction of blood flow. It is a leading cause of death in industrialized countries as it causes heart attacks, strokes, and peripheral vascular disease. Pathogenesis of the atherosclerotic lesion (atheroma) relies on the accumulation of cholesterol-containing low-density lipoproteins (LDL) and on changes of artery endothelium that becomes adhesive for monocytes and lymphocytes. Immunomediated inflammatory response stimulated by lipoprotein oxidation, cytokine secretion and release of pro-inflammatory mediators, worsens the pathological context by amplifying tissue damage to the arterial lining and increasing flow-limiting stenosis. Formation of thrombi upon rupture of the endothelium and the fibrous cup may also occur, triggering thrombosis often threatening the patient’s life. Purinergic signaling, i.e., cell responses induced by stimulation of P2 and P1 membrane receptors for the extracellular nucleotides (ATP, ADP, UTP, and UDP) and nucleosides (adenosine), has been implicated in modulating the immunological response in atherosclerotic cardiovascular disease. In this review we will describe advancements in the understanding of purinergic modulation of the two main immune cells involved in atherogenesis, i.e., monocytes/macrophages and T lymphocytes, highlighting modulation of pro- and anti-atherosclerotic mediated responses of purinergic signaling in these cells and providing new insights to point out their potential clinical significance.
Highlights
Atherosclerosis is a chronic inflammatory disease of the arteries, characterized by the development of characteristic lesions named atheromatous plaques [1, 2]
Circulating monocytes are captured by the activated endothelium and undergo differentiation into macrophages and changing their phenotype according to stages of the atherosclerotic process
Extracellular adenosine diphosphate (ATP) is among stimuli that potently activate NLRP3, it is very promising for therapeutic purposes the observation that deficiency of a single purinergic receptor, namely the P2X7 subtype, is sufficient to block NLRP3 inflammasome and ameliorate the clinical picture of atherosclerosis in mice [122]
Summary
Atherosclerosis is a chronic inflammatory disease of the arteries, characterized by the development of characteristic lesions named atheromatous plaques [1, 2]. Upon expression of scavenger receptors, engulfment of oxLDL and migration to the intima, circulating monocytes become macrophages (foam cells) that dying in the plaque release engulfed lipids (Figure 1, topics 3, 4). Circulating monocytes are captured by the activated endothelium and undergo differentiation into macrophages and changing their phenotype according to stages of the atherosclerotic process. They perform different tasks ranging from perception of danger signals, engulfment of lipids and dead cells, secretion of inflammatory (ROS, activating cytokines) and proresolving molecules [12]. Antigen presentation by lesional macrophages and DC enables T cells to recognize antigens promoting the pro-inflammatory response underlying atherosclerosis (Figure 1, topic 10). We will highlight the potential of purinergic receptor agonists and antagonists for new therapeutic strategies to treat atherosclerosis
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