CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction

Abstract

ML. CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol 300: H1418 -H1426, 2011. First published February 4, 2011 doi:10.1152/ajpheart.01002.2010, chemokine homing of inflammatory cells into the injured left ventricle (LV) regulates ventricular remodeling, in part by stimulating the extracellular matrix response. The CC chemokine receptor 5 (CCR5) is a key chemokine receptor expressed on macrophages, and CCR5 ligands are highly upregulated post-MI. We hypothesized that deletion of CCR5 would attenuate adverse remodeling by decreasing inflammatory cell recruitment. Accordingly, we examined LV function, macrophage recruitment and activation, and collagen content in wild-type (WT, n ϭ 25) and CCR5 null (n ϭ 33) mice at 7 days post-MI. Both groups had similar infarct sizes (44 Ϯ 2% in WT and 42 Ϯ 2% in CCR5 null; P ϭ 0.37). However, the LV remodeling index (end diastolic volume/LV mass) increased to a larger extent in CCR5 null (1.28 Ϯ 0.08 l/mg for CCR5 null and 1.02 Ϯ 0.06 l/mg for WT; P Ͻ 0.05). Although numbers of infiltrated macrophages were similar in WT and CCR5 null mice, CCR5-deficient macrophages isolated from the infarct zone displayed Ͼ50% decrease in gene expression levels of proinflammatory activation markers (interleukin-1␤, interleukin-6, and tumor necrosis factor-␣), as well as anti-inflammatory activation markers (arginase 1, CD163, mannose receptor, and transforming growth factor-␤1) compared with WT (all P Ͻ 0.05). Concomitant with the reduced macrophage activation, heat shock protein-47 and collagen type I precursor levels in the infarct region decreased in the CCR5 null (1.2 Ϯ 0.3 units in the CCR5 null and 2.3 Ϯ 0.4 units in the WT; P Ͻ 0.05), while collagen fragments increased (88.3 Ϯ 5.9 units in the CCR5 null and 32.7 Ϯ 8.5 units in the WT; P Ͻ 0.05). We conclude that CCR5 deletion impairs LV remodeling by hindering macrophage activation, which stimulates an imbalance in collagen metabolism and increases the remodeling index. inflammation; matrix metalloproteinases; CC chemokines CC CHEMOKINES CONTROL IMMUNE responses by regulating the recruitment and activation of leukocytes. CC chemokine ligand 2 (CCL2; monocyte chemotactic protein-1), CCL3 (macrophage inflammatory protein-1␣), CCL4 (macrophage inflammatory protein-1␤), and CCL5 (regulated on activation normal T-expressed and presumably secreted) chemokines, in particular, have monocyte chemotactic activities, and neutralization of these chemokines and downstream signaling results in reduced macrophage infiltration to sites of inflammation (2, 3, 15). In vivo, CCL2, CCL3, and CCL5 have been implicated in left ventricular (LV) remodeling, as levels of these CC chemokines increase post-myocardial infarction (MI) in both animal models and humans, and serum levels increase further in patients who progress to heart failure (5, 6, 24).CC chemokines receptor 5 (CCR5) is the major coreceptor for human immunodeficiency virus infection of macr...

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