Université Paris Descartes, INSERM UMR-S970, Paris Cardiovascular Research Center, Hôpital Européen Georges Pompidou. Paris, France.
Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2206-13. doi: 10.1161/ATVBAHA.112.254409. Epub 2012 Jul 12.
Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction.
D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6(-/-)) infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ischemic heart. D6(-/-) mice were cardiac rupture prone after myocardial infarction, and functional analysis revealed that D6(-/-) hearts had features of adverse remodeling with left ventricle dilation and reduced ejection fraction. Bone marrow chimera experiments showed that leukocyte-borne D6 had no role in this setting, and that leukocyte-specific chemokine (C-C motif) receptor 2 deficiency rescued the adverse phenotype observed in D6(-/-) mice.
We show for the first time that the chemokine decoy receptor D6 limits CC-chemokine-dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction.
缺血区白细胞浸润是心肌梗死的一个标志，大量固有免疫细胞的浸润已被证明可促进不良重构和心脏破裂。缺血性心脏中炎症细胞的募集高度依赖于 CC 趋化因子家族及其受体。在这里，我们假设趋化因子诱饵受体 D6 特异性结合和清除炎症性 CC 趋化因子，可能限制梗塞后炎症和不良心脏重构。
D6 在人和鼠梗死心肌中表达。在心肌梗死的鼠模型中，D6 缺乏导致缺血心肌中趋化因子（C-C 基序）配体 2 和趋化因子（C-C 基序）配体 3 水平升高。D6 缺陷（D6(-/-)）梗死显示缺血心肌中致病性中性粒细胞和 Ly6Chi 单核细胞浸润增加，与基质金属蛋白酶-9 和基质金属蛋白酶-2 活性增强相关。D6(-/-) 小鼠在心肌梗死后易发生心脏破裂，功能分析显示 D6(-/-) 心脏具有不良重构的特征，表现为左心室扩张和射血分数降低。骨髓嵌合体实验表明，白细胞携带的 D6 在这种情况下没有作用，并且白细胞特异性趋化因子（C-C 基序）受体 2 缺乏可挽救 D6(-/-) 小鼠观察到的不良表型。
我们首次表明，趋化因子诱饵受体 D6 限制 CC 趋化因子依赖性致病性炎症，是心肌梗死后适当心脏重构所必需的。
