Conjugated Linoleic Acid Targets β2 Integrin Expression To Suppress Monocyte Adhesion

Abstract

Chronic recruitment of monocytes and their subsequent migration through the activated endothelium contribute to atherosclerotic plaque development. Integrin-mediated leukocyte adhesion is central to this process. Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis via modulation of monocyte/macrophage function. Understanding the mechanisms through which CLA mediates its atheroprotective effect may help to identify novel pathways that limit or reverse atherosclerosis. In this study, we identified a novel mechanism through which CLA alters monocyte function. We show that CLA inhibits human peripheral blood monocyte cell adhesion to activated endothelial cells via loss of CD18 expression, the β2 chain of LFA-1 and Mac-1 integrins. In addition, using a static-adhesion assay, we provide evidence that CLA prevents monocytes from binding to ICAM-1 and subsequently reduces the capacity of these cells to polarize. CXCL12–CXCR4 interactions induce a conformational change in β2 integrins, facilitating leukocyte adhesion. In this study, we demonstrate that CLA inhibits CXCR4 expression, resulting in a failure of monocytes to directionally migrate toward CXCL12. Finally, using intravital microscopy, we show that, during CLA-induced regression of pre-established atherosclerosis in ApoE−/− mice, there is reduced leukocyte adhesion and decreased CD18 expression on Gr1+/CD115+ proinflammatory monocytes. In summary, the data presented describe a novel functional role for CLA in the regulation of monocyte adhesion, polarization, and migration.

The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease

“…Further, intercellular adhesion molecule (ICAM) 1, TNF-α and interleukin (IL) 6 mRNA expression as well as superoxide generation in the aorta declined in mice treated with GYY4137 (Liu et al, 2013). Similarly, and again paralleling in vitro studies with human monocytes, CLA treatment of Apoe −/− mice with already pre-established atherosclerosis induced lesion regression by reducing leukocyte adhesion and decreasing CD18 expression on classical monocytes (De Gaetano et al, 2013). …”

“…In addition, CLA reduced CXCR4 expression, resulting in an only minor initiation of “inside out” signaling. As a result, partial, but incomplete, activation of β 2-integrins further reduces adherence of leukocytes and their migration to CXCL12 (De Gaetano et al, 2013). …”

Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload–Induced Heart Failure

“…Multiple studies over the years have identified ICAM1 as a critical regulator of leukocyte arrest and transendothelial migration to allow leukocyte tissue infiltration in cardiovascular disease . In the human heart, endothelial ICAM1 is upregulated after myocardial infarction, correlating with high infiltration of inflammatory leukocytes .…”

Different monocyte phenotypes result in proresolving macrophages in conjugated linoleic acid‐induced attenuated progression and regression of atherosclerosis

“…Lipid mediators, resolvin D2, and maresin-1 inhibited expansion of the necrotic core, accumulation of macrophages, induced plaque stability, and shifted the M1:M2 macrophage ratio toward a reparative phenotype (42). Our previous work has shown that CLA 80:20 promotes anti-inflammatory macrophages, reduces inflammatory mediators, and alters monocyte responses to atherosclerotic stimuli (26,27,30,31). In this present study, novel phenotypic profiling of monocyte/macrophage phenotypes was performed in an early model of atherosclerosis with dietary CLA 80:20 blend.…”

“…Arbonés-Mainar et al showed that cis-9:trans-11-CLA inhibited atherogenic development, whereas Mitchell et al (28,29) reported trans-10:cis-12-CLA inhibited lesion development despite adverse CV profiles. We have previously interrogated the effects of CLA on macrophage phenotype and function and have shown that CLA 80:20 induces an atheroprotective M2 macrophage phenotype (27) and limits foam cell formation, monocyte adhesion, and the inflammatory phenotype associated with monocytes and macrophages in atherosclerotic disease (30,31).…”