Survival and Cardiac Remodeling After Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor-Associated Kinase-4 Signaling A Regulator of Bone Marrow-Derived Dendritic Cells
Survival and Cardiac Remodeling After Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor-Associated Kinase-4 Signaling A Regulator of Bone Marrow-Derived Dendritic Cells
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DOI：
10.1161/circulationaha.109.865956
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发表时间：
2009-10-06
期刊：
影响因子：
37.8
通讯作者：
Liu, Peter P.
中科院分区：
文献类型：
--
作者：
Maekawa, Yuichiro;Mizue, Nobuo;Liu, Peter P.
背景-先天免疫系统在心肌梗死（MI）后的炎症过程中起重要作用。白细胞介素-1受体相关激酶-4（IRAK-4）位于Toll/白细胞介素-1受体信号转导的下游，在调节先天性免疫应答中具有重要作用。本研究旨在确定IRAK-4负责心脏炎症过程的机制，从而影响MI后的左心室重塑。方法和结果实验性MI在IRAK-4（-/-）和野生型小鼠左冠状动脉结扎。具有IRAK-4靶向缺失的小鼠在MI后4周具有改善的存活率。IRAK-4（-/-）小鼠还表现出心肌梗死心肌中心脏扩张减弱和炎症减少，这与抑制核因子-κ B和c-Jun N-末端激酶激活介导的促炎性和Th 1细胞因子表达减少有关。IRAK-4（-/-）小鼠的CD 45（+）白细胞和CD 11 c（+）树突状细胞浸润较少，细胞凋亡受到抑制，纤维化和一氧化氮产生减少。IRAK-4（-/-）小鼠心肌梗死后心脏树突状细胞相对不成熟或功能幼稚，因为它们表现出较少的细胞因子和共刺激分子基因表达。此外，IRAK-4（-/-）树突状细胞具有较低的动员能力。将野生型来源的骨髓树突状细胞转移到IRAK-4（-/-）小鼠中用于功能性树突状细胞重建否定了存活优势，并减少了在MI后28天用IRAK-4（-/-）小鼠观察到的心脏扩张。4通过钝化有害的骨骼来修饰宿主的炎症过程，对MI后的存活和左心室重构具有有利的作用心肌缺血后骨髓树突状细胞动员。（循环。2009;120：1401-1414）。
Background-The innate immune system greatly contributes to the inflammatory process after myocardial infarction (MI). Interleukin-1 receptor-associated kinase-4 (IRAK-4), downstream of Toll/interleukin-1 receptor signaling, has an essential role in regulating the innate immune response. The present study was designed to determine the mechanism by which IRAK-4 is responsible for the cardiac inflammatory process, which consequently affects left ventricular remodeling after MI.Methods and Results-Experimental MI was created in IRAK-4(-/-) and wild-type mice by left coronary ligation. Mice with a targeted deletion of IRAK-4 had an improved survival rate at 4 weeks after MI. IRAK-4(-/-) mice also demonstrated attenuated cardiac dilation and decreased inflammation in the infarcted myocardium, which was associated with less proinflammatory and Th1 cytokine expression mediated by suppression of nuclear factor-kappa B and c-Jun N-terminal kinase activation. IRAK-4(-/-) mice had fewer infiltrations of CD45(+) leukocytes and CD11c(+) dendritic cells, inhibition of apoptosis, and reduced fibrosis and nitric oxide production. Cardiac dendritic cells in IRAK-4(-/-) mice were relatively immature or functionally nave after MI in that they demonstrated less cytokine and costimulatory molecule gene expression. Furthermore, IRAK-4(-/-) dendritic cells have less mobilization capacity. Transfer of wild type-derived bone marrow dendritic cells into IRAK-4(-/-) mice for functional dendritic cell reconstitution negated the survival advantage and reduced the cardiac dilation observed with IRAK-4(-/-) mice at 28 days after MI.Conclusions-Deletion of IRAK-4 has favorable effects on survival and left ventricular remodeling after MI through modification of the host inflammatory process by blunting the detrimental bone marrow dendritic cells mobilization after myocardial ischemia. (Circulation. 2009;120:1401-1414.)