CCR5 signaling suppresses inflammation and attenuates adverse remodeling in healing myocardial infarcts.

Chemokine‐mediated interactions may regulate chemotactic recruitment of leukocyte subsets and modulate cellular responses in healing infarcts. We hypothesized that CCR5, a receptor for the CC chemokines MIP‐1α, MIP‐1β and RANTES may play a crucial role in the post‐infarction inflammatory response. Morphometric, molecular and echocardiographic endpoints were compared in WT and CCR5 ‐/‐ mice undergoing reperfused infarction protocols. MIP‐1α, MIP‐1β and CCR5 were markedly induced in WT infarcts; however, RANTES mRNA was not upregulated. Neutrophil and macrophage density was comparable in CCR5 ‐/‐ and WT infarcts. However, in the absence of CCR5, expression of the pro‐inflammatory cytokines TNF‐α, IL‐1β and IL‐6 and the chemokines MIP‐1α and MIP‐1β was significantly increased after 6‐24h of reperfusion. CCR5 ‐/‐ hearts exhibited enhanced ventricular dilation following infarction associated with increased levels of MMP‐8 and MMP‐9 and reduced TIMP‐1 expression. The surprising accentuation of the inflammatory response in CCR5 ‐/‐ infarcts was associated with reduced foxp3 mRNA levels suggesting impaired recruitment of regulatory T cells (Tregs). The anti‐inflammatory effects of CCR5 in healing infarcts may be mediated through selective recruitment of leukocyte subsets with suppressive properties (R01 HL‐76246 and HL‐85440).