Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair
Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair
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DOI：
10.1096/fj.201700450r
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发表时间：
2018-01-01
期刊：
影响因子：
4.8
通讯作者：
Thorp，Edward B.
中科院分区：
文献类型：
--
作者：
Dehn，Shirley;Thorp，Edward B.
心肌梗死（MI）后的吞噬作用是心脏修复的先决条件。募集的单核细胞清除坏死的心肌细胞并分化为心脏巨噬细胞。一些研究将心脏巨噬细胞上的凋亡细胞受体与组织修复联系起来。然而，首先与心脏实质相互作用的前体单核细胞吞噬受体的贡献尚不清楚。在心脏 Ly6cHI 单核细胞上检测到分化清道夫受体簇 (CD)36 蛋白，骨髓来源的 Cd36 对于死亡心肌细胞的早期吞噬作用以及永久性冠状动脉结扎后雌性和雄性小鼠梗塞面积的缩小至关重要。 Cd36 缺乏导致心脏巨噬细胞中吞噬受体 Mertk 和核受体 Nr4a1 的表达减少，后者先前被证明是吞噬细胞生存所必需的。 Nr4a1是吞噬作用诱导的Mertk表达所必需的，Nr4a1蛋白直接与Mertk基因调控元件结合。为了测试 Cd36-Mertk 轴的总体贡献，在 Cd36−/− Mertk−/− 双敲除小鼠中诱导 MI，并导致心肌破裂增加。这些数据表明单核细胞 CD36 有助于减轻早期梗塞面积以及向 Mertk 依赖性巨噬细胞功能的转变。在缺乏 Cd36 和 Mertk 的情况下，心肌破裂的增加强调了组织损伤期间吞噬作用的生理意义。—Dehn, S., Thorp, E. B. 心肌梗塞的早期吞噬作用和诱导 Nr4a1 依赖性心脏修复机制需要骨髓受体 CD36。
Phagocytosis after myocardial infarction (MI) is a prerequisite to cardiac repair. Recruited monocytes clear necrotic cardiomyocytes and differentiate into cardiac macrophages. Some studies have linked apoptotic cell receptors on cardiac macrophages to tissue repair; however, the contribution of precursor monocyte phagocytic receptors, which are the first to interact with the cardiac parenchyma, is unclear. The scavenger receptor cluster of differentiation (CD)36 protein was detected on cardiac Ly6cHI monocytes, and bone marrow–derived Cd36 was essential for both early phagocytosis of dying cardiomyocytes and for smaller infarct sizes in female and male mice after permanent coronary ligation. Cd36 deficiency led to reduced expression of phagocytosis receptor Mertk and nuclear receptor Nr4a1 in cardiac macrophages, the latter previously shown to be required for phagocyte survival. Nr4a1 was required for phagocytosis-induced Mertk expression, and Nr4a1 protein directly bound to Mertk gene regulatory elements. To test the overall contribution of the Cd36-Mertk axis, MI was induced in Cd36−/− Mertk−/− double-knockout mice and led to increases in myocardial rupture. These data implicate monocyte CD36 in the mitigation of early infarct size and transition to Mertk-dependent macrophage function. Increased myocardial rupture in the absence of both Cd36 and Mertk underscore the physiologic significance of phagocytosis during tissue injury.—Dehn, S., Thorp, E. B. Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair.