CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells.
CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells.
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DOI：
10.2353/ajpath.2010.090759
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发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Frangogiannis NG
中科院分区：
文献类型：
--
作者：
Dobaczewski M;Xia Y;Bujak M;Gonzalez-Quesada C;Frangogiannis NG
心肌梗死引发了与心脏重塑有关的炎症反应。心脏修复依赖于抑制炎症和防止过度基质降解的调节机制。梗死心脏中趋化因子诱导介导具有不同性质的白细胞亚群的募集。我们证明，通过CC趋化因子受体5（CCR 5）的信号传导可以防止不受控制的梗死后炎症，并通过招募抑制性单核细胞来防止不良重塑。CCR 5及其配体巨噬细胞炎性蛋白（MIP）−1α和MIP-1β在梗死小鼠心肌中显著诱导。此外，几乎40%的浸润梗死的单核细胞表达CCR 5。CCR 5 −/−小鼠在梗死中表现出促炎细胞因子和趋化因子表达的显著上调。在野生型梗死中，CCR 5+单核细胞具有抗炎特性，表达的IL-10水平高于CCR 5 −细胞。相反，从CCR 5 −/−梗死中分离的单核细胞具有降低的IL-10表达。此外，在缺乏CCR 5的情况下增强的炎症与CD 4 +/foxp 3+调节性T细胞（TcR）的募集受损相关。CCR 5 + Treg亚群表现出增加的IL-10表达，反映了有效的抗炎活性。CCR 5 −/−梗死中的炎症加重与基质金属蛋白酶（MMP）表达增加、TIMP水平降低以及MMP-2和MMP-9活性增强相关，导致心脏扩张恶化。这些结果表明，CCR 5介导的Treg募集可以抑制梗死后炎症，防止过度基质降解和减弱不良重塑。
Myocardial infarction triggers an inflammatory reaction that is involved in cardiac remodeling. Cardiac repair is dependent on regulatory mechanisms that suppress inflammation and prevent excessive matrix degradation. Chemokine induction in the infarcted heart mediates recruitment of leukocyte subsets with distinct properties. We demonstrate that signaling through the CC chemokine receptor 5 (CCR5) prevents uncontrolled postinfarction inflammation and protects from adverse remodeling by recruiting suppressive mononuclear cells. CCR5 and its ligands macrophage inflammatory protein (MIP)−1α and MIP-1β were markedly induced in the infarcted mouse myocardium. In addition, almost 40% of the mononuclear cells infiltrating the infarct expressed CCR5. CCR5−/− mice exhibited marked upregulation of proinflammatory cytokine and chemokine expression in the infarct. In wild-type infarcts CCR5+ mononuclear cells had anti-inflammatory properties, expressing higher levels of IL-10 than CCR5− cells. In contrast, mononuclear cells isolated from CCR5−/− infarcts had reduced IL-10 expression. Moreover, enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of CD4+/foxp3+ regulatory T cells (Tregs). The CCR5+ Treg subset exhibited increased IL-10 expression, reflecting potent anti-inflammatory activity. Accentuated inflammation in CCR5−/− infarcts was associated with increased matrix metalloproteinase (MMP) expression, reduced TIMP levels, and enhanced MMP-2 and MMP-9 activity, resulting in worse cardiac dilation. These results suggest that CCR5-mediated Treg recruitment may restrain postinfarction inflammation, preventing excessive matrix degradation and attenuating adverse remodeling.
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