Endogenous IRAK-M attenuates postinfarction remodeling through effects on macrophages and fibroblasts.
Endogenous IRAK-M attenuates postinfarction remodeling through effects on macrophages and fibroblasts.
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DOI：
10.1161/atvbaha.112.300310
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Frangogiannis NG
中科院分区：
文献类型：
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作者：
Chen W;Saxena A;Li N;Sun J;Gupta A;Lee DW;Tian Q;Dobaczewski M;Frangogiannis NG
有效的梗塞后修复需要及时抑制先天免疫信号，以防止不受控制的炎症对心脏几何结构和功能造成灾难性后果。在巨噬细胞中，白细胞介素受体相关激酶 (IRAK)-M 充当功能诱饵，防止不受控制的 TLR/白细胞介素-1 介导的反应。我们的研究调查了 IRAK-M 作为梗塞后炎症反应负调节剂和心脏重塑调节剂的作用。在WT小鼠梗塞中，IRAK-M在浸润巨噬细胞和成纤维细胞中上调，表现出双相反应。与野生型动物相比，梗死的 IRAK-M −/− 小鼠的不良重塑增强，收缩功能障碍更严重。然而，各组之间的急性梗塞面积相当。 IRAK-M −/− 动物的不良重塑与心肌炎症和蛋白酶激活增强有关。 IRAK-M 的保护作用涉及巨噬细胞和成纤维细胞的表型调节。 IRAK-M −/− 梗塞显示促炎性 CD11b+/Ly6Chi 单核细胞浸润增加；从 IRAK-M 无效梗塞中收获的白细胞表现出细胞因子表达增强。在体外，IRAK-M 表达在细胞因子刺激的小鼠心脏成纤维细胞中上调，并抑制其基质降解特性，而不影响其炎症活性。内源性 IRAK-M 减弱不良的梗死后重塑，抑制白细胞炎症活性，同时抑制成纤维细胞介导的基质降解。
Effective post-infarction repair requires timely suppression of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function. In macrophages, Interleukin Receptor-Associated Kinase (IRAK)-M acts as a functional decoy preventing uncontrolled TLR/Interleukin-1-mediated responses. Our study investigates the role of IRAK-M as a negative regulator of the post-infarction inflammatory response and as a modulator of cardiac remodeling. In WT mouse infarcts IRAK-M was upregulated in infiltrating macrophages and fibroblasts exhibiting a biphasic response. When compared to wildtype animals, infarcted IRAK-M −/− mice had enhanced adverse remodeling and worse systolic dysfunction; however, acute infarct size was comparable between groups. Adverse remodeling in IRAK-M −/− animals was associated with enhanced myocardial inflammation and protease activation. The protective actions of IRAK-M involved phenotypic modulation of macrophages and fibroblasts. IRAK-M −/− infarcts showed increased infiltration with pro-inflammatory CD11b+/Ly6Chi monocytes; leukocytes harvested from IRAK-M null infarcts exhibited accentuated cytokine expression. In vitro, IRAK-M expression was upregulated in cytokine-stimulated murine cardiac fibroblasts and suppressed their matrix-degrading properties without affecting their inflammatory activity. Endogenous IRAK-M attenuates adverse post-infarction remodeling suppressing leukocyte inflammatory activity, while inhibiting fibroblast-mediated matrix degradation.