Chemokines Control Mobilization, Recruitment, and Fate of Monocytes in Atherosclerosis

Abstract

Abstract-Atherosclerosis is a chronic inflammatory disease of large arteries and, among others, characterized by continuous influx of monocytes into the subendothelial space, subsequent macrophage accumulation, and foam cell formation. Chemokines and their receptors tightly orchestrate monocyte trafficking and fate from birth to death. This brief review summarizes our current understanding of the interplay between monocytes and chemokines entertaining crucial processes in atherosclerosis development, progression, and regression. Drechsler et al Monocytes in Atherosclerosis 1051contribute to arterial monocyte accumulation. Under steadystate conditions, classical monocyte homeostasis is tightly regulated by the CCL2/CCR2 axis and mice deficient for CCR2 display severely reduced counts of circulating classical monocytes. 12 Under acute inflammatory conditions, murine classical monocytes are mobilized from the bone marrow in a CCL2/ CCR2-and CCL7/CCR2-dependent fashion. 12,13 However, in the context of atherosclerosis, these axes seem to be of minor relevance as plasma concentrations of CCL2 and CCL7 do not increase in apolipoprotein E-deficient (Apoe −/− ) mice fed a high-fat diet. 6 Furthermore, although mice deficient of CCR2 display a markedly reduced number of circulating classical monocytes already under steady-state conditions, monocyte counts in these mice do still increase under hypercholesterolemia. 6 Instead, the CXCL1/CXCR2 axis has been unraveled to be of major importance in classical monocytosis induced by high-fat diet as plasma CXCL1 increases under such conditions and CXCL1 neutralization abrogates expansion of circulating classical monocytes.6 As a consequence, injection of CXCL1 neutralizing antibodies reduces lesional macrophage counts and resulting lesion sizes are smaller. 6Beside direct mobilization of classical monocytes from the bone marrow, a more recent study links cholesterol efflux via ATP-binding cassette transporters with hematopoietic stem and multipotential progenitor cell mobilization and extramedullary proliferation.14 This might be of high interest as the spleen has been identified as reservoir for classical monocytes, which can be readily mobilized during inflammation. 15 In accordance with this finding, splenectomized mice failed to develop a monocytosis under acute inflammatory conditions 15 and splenic monocytes give rise to lesional macrophages. 16 Of note, several chemokines, including CCL3 and CXCL8, have been shown to suppress hematopoietic stem and multipotential progenitor cell proliferation and may thus potentially counteract hematopoiesis under conditions of hypercholesterolemia. monocyte mobilization from sites of production, the lesion phenotype observed in CCR2-deficient mice may be ascribed to low circulating monocyte numbers rather than inhibited recruitment. 6The majority of chemotactic molecules is derived from circulating platelets and neutrophils or from tissue resident cells such as endothelial cells and macrophages. In fact, the importance of platelets in a...

Protective Aptitude of Annexin A1 in Arterial Neointima Formation in Atherosclerosis-Prone Mice—Brief Report

“…10 Arterial macrophage accumulation is controlled by different mechanisms, including apoptosis, recruitment, and proliferation. 11 In previous work, it has been shown that AnxA1 and its N-terminal fragment Ac2-26 counteract chemokine-induced integrin activation by inhibition of Rap1 activation in monocytes and, therefore, restrains adhesion to large arteries. 5 Consequently, enhanced recruitment of monocytes in AnxA1-deficient mice may contribute to the phenotype observed in the present study.…”

Reactive Oxygen Species Generation and Atherosclerosis

“…4,83,84 At the beginning of atherosclerosis, monocytes, which are attracted by the chemokines secreted by resident vascular cells, migrate into the subendothelial area where they differentiate into macrophages on growth factors stimulation. 83 In the atherosclerotic lesions, macrophages ingest oxidized LDL through scavenger receptors and become lipid-laden foam cells.…”

“…[1][2][3] An inflamed endothelium recruits inflammatory cells, such as monocytes, via the expression of various mediators and chemokines. [4][5][6] This, in addition to the accumulation of cholesterol and smooth muscle cells (SMCs) in the intima, leads to the transformation of monocytes into foam cells, which consume dead cells and lipids. [7][8][9] The atherogenic process involves multiple cell types, that is, endothelial cells (ECs), 10 SMCs, 11 immune cells, 12 and stem/progenitor cells, 13 in which levels of both intracellular and extracellular reactive oxygen and nitrogen species play a fundamental role in vascular cell homoeostasis and eventually affects the development of atherosclerosis.…”

Monocytes and macrophages in cardiac injury and repair

“…Furthermore, CXCL1/CXCR2 signaling also contributes to blood monocytosis. In mice fed a highcholesterol diet, CXCL1 neutralization dampens expansion of blood Ly6C high monocytes (31).…”