Mechanisms of Myeloid Cell Modulation of Atherosclerosis.

Abstract

Inflammation furnishes a series of pathogenic pathways that couple the risk factors for atherosclerosis with altered behavior of the intrinsic cells of the arterial wall, endothelium, and smooth muscle and promote the disease and its complications. Myeloid cells participate critically in all phases of atherosclerosis from initiation through progression, and ultimately the thrombotic consequences of this disease. Foam cells, lipid-laden macrophages, constitute the hallmark of atheromata. Much of the recent expansion in knowledge of the roles of myeloid cells in atherosclerosis revolves around the functional contributions of subsets of monocytes, precursors of macrophages, the most abundant myeloid cells in the atheroma. Proinflammatory monocytes preferentially accumulate in nascent atherosclerotic plaques. The most dramatic manifestations of atherosclerosis result from blood clot formation. Myocardial infarction, ischemic stroke, and abrupt limb ischemia all arise primarily from thrombi that complicate atherosclerotic plaques. Myeloid cells contribute pivotally to triggering thrombosis, for example, by elaborating enzymes that degrade the plaque's protective extracellular matrix, rendering it fragile, and by producing the potent procoagulant tissue factor. While most attention has focused on mononuclear phagocytes, the participation of polymorphonuclear leukocytes may aggravate local thrombus formation. Existing therapies such as statins may exert some of their protective effects by altering the functions of myeloid cells. The pathways of innate immunity that involve myeloid cells provide a myriad of potential targets for modifying atherosclerosis and its complications, and provide a fertile field for future attempts to address the residual burden of this disease, whose global prevalence is on the rise.