Abstract 5055: CC Chemokine Receptor 5 Signaling Suppresses Inflammation and Attenuates Adverse Remodeling Following Myocardial Infarction by Recruiting Regulatory T Cells
Myocardial infarction triggers an inflammatory reaction that is critically involved in the pathogenesis of cardiac remodeling. Optimal cardiac repair is dependent on regulatory mechanisms that suppress inflammation preventing excessive matrix degradation. Chemokines are rapidly induced in the healing infarct mediating recruitment of leukocyte subsets with distinct properties. CCR5, the receptor for the CC chemokines MIP-1α, MIP-1β and RANTES plays an important role in immunoinflammatory responses. We hypothesized that CCR5 signaling may regulate the inflammatory response following myocardial infarction playing a role in the development of cardiac remodeling. CCR5 and its ligands MIP-1α and MIP-1β were markedly induced in reperfused mouse infarcts. Flow cytometry demonstrated that 38.3%+3.75 of the mononuclear cells infiltrating the infarcted myocardium after 24h of reperfusion expressed CCR5. CCR5 −/− mice and WT animals showed comparable macrophage and neutrophil infiltration in the infarct; however, CCR5 absence was associated with marked upregulation of pro-inflammatory cytokine (IL-1β, TNF-α and IL-6) and chemokine (MIP-2, MIP-1α, -β and IP-10) mRNA expression in the infarcted myocardium. CCR5+ mononuclear cells isolated from WT infarcts had anti-inflammatory properties exhibiting higher expression of the inhibitory cytokine IL-10 than CCR5- cells. In addition, mononuclear cells isolated from CCR5 −/− infarcts had reduced IL-10 expression. Enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of foxp3+ regulatory T cells (Tregs), a CD4+ lymphocyte subpopulation with suppressive properties (Tregs as a percentage of T cells: WT 13.1%+ 1.1 vs. KO 7.2%+ 1.1; p<0.05). In WT mice the CCR5+ subset of Tregs exhibited enhanced expression of IL-10 reflecting potent anti-inflammatory activity. Enhanced inflammation in CCR5 −/− infarcts was associated with increased MMP and decreased TIMP expression, resulting in accentuated cardiac dilation (LVEDV: WT 52.99+2.43 mm3 vs. KO 65.13+4.53 mm3; p=0.02) without affecting the size of the infarct. CCR5-mediated recruitment of Tregs may restrain post-infarction inflammation preventing excessive matrix degradation and attenuating adverse remodeling.