Cardiac Resident Macrophage-Derived Legumain Improves Cardiac Repair by Promoting Clearance and Degradation of Apoptotic Cardiomyocytes After Myocardial Infarction
Cardiac Resident Macrophage-Derived Legumain Improves Cardiac Repair by Promoting Clearance and Degradation of Apoptotic Cardiomyocytes After Myocardial Infarction
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心脏巨噬细胞来源的豆类蛋白通过促进心肌梗死后凋亡心肌细胞的清除和降解来改善心脏修复
DOI：
10.1161/circulationaha.121.057549
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发表时间：
2022-05-17
期刊：
影响因子：
37.8
通讯作者：
Ge, Junbo
中科院分区：
文献类型：
--
作者：
Jia, Daile;Chen, Siqin;Ge, Junbo
背景：心脏巨噬细胞是自我维持的，起源于胚胎造血。心肌梗死后，心肌巨噬细胞负责有效清除和降解凋亡的心肌细胞（efferocytosis）。这个过程是炎症消退和组织修复所必需的；然而，潜在的分子机制仍然未知。因此，我们旨在确定心肌梗死期间心脏巨噬细胞持续清除和降解吞噬酶体货物的机制。方法：Lgmn（-/-）、Lgmn（F/F）等多种转基因小鼠；LysM (Cre) Lgmn (F / F);Cx3cr1(相信),Lgmn (F / F);采用Lyve（Cre）和腺病毒基因转染心肌巨噬细胞Lgmn过表达的方法，探讨Lgmn在心肌梗死中的功能意义。流式细胞术和实时定量聚合酶链反应检测免疫细胞滤过和炎症反应。采用免疫组织化学和实时定量聚合酶链反应分析了缺血性心肌病患者和健康对照组心脏组织中legumain （Lgmn）的表达。结果：我们发现Lgmn是心脏巨噬细胞特异性表达的基因。Lgmn缺乏导致心功能明显恶化，并伴有心肌细胞凋亡的积累和边界区体内efferocytosis指数的降低。它还导致由于细胞内钙动员缺陷导致的胞质钙减少。此外，继发性凋亡心肌细胞周围lc3 - ii依赖性吞噬体的形成被破坏。此外，Lgmn缺乏增加mhc - ii高CCR2（+）巨噬细胞的浸润和mhc - ii低CCR2（+）单核细胞的募集，下调抗炎介质白介素-10和转化生长因子- β，上调促炎介质白介素-1 β、肿瘤坏死因子- α、白介素-6和干扰素- γ。结论：我们的研究结果直接将胞饮作用与心脏伤口愈合联系起来，并确定Lgmn是急性炎症消退和器官功能之间的重要联系。
Background: Cardiac resident macrophages are self-maintaining and originate from embryonic hematopoiesis. After myocardial infarction, cardiac resident macrophages are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes (efferocytosis). This process is required for inflammation resolution and tissue repair; however, the underlying molecular mechanisms remain unknown. Therefore, we aimed to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. Methods: Multiple transgenic mice such as Lgmn(-/-), Lgmn(F/F); LysM(Cre), Lgmn(F/F); Cx3cr1(CreER), Lgmn(F/F); Lyve(Cre), and cardiac macrophage Lgmn overexpression by adenovirus gene transfer were used to determine the functional significance of Lgmn in myocardial infarction. Immune cell filtration and inflammation were examined by flow cytometry and quantitative real-time polymerase chain reaction. Moreover, legumain (Lgmn) expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction in the cardiac tissues of patients with ischemic cardiomyopathy and healthy control subjects. Results: We identified Lgmn as a gene specifically expressed by cardiac resident macrophages. Lgmn deficiency resulted in a considerable exacerbation in cardiac function, accompanied by the accumulation of apoptotic cardiomyocytes and a reduced index of in vivo efferocytosis in the border area. It also led to decreased cytosolic calcium attributable to defective intracellular calcium mobilization. Furthermore, the formation of LC3-II-dependent phagosome around secondary-encountered apoptotic cardiomyocytes was disabled. In addition, Lgmn deficiency increased infiltration of MHC-IIhigh CCR2(+) macrophages and the enhanced recruitment of MHC-IIlow CCR2(+) monocytes with downregulation of the anti-inflammatory mediators, interleukin-10, and transforming growth factor-beta and upregulationof the proinflammatory mediators interleukin-1 beta, tumor necrosis factor-alpha, interleukin-6, and interferon-gamma. Conclusions: Our results directly link efferocytosis to wound healing in the heart and identify Lgmn as a significant link between acute inflammation resolution and organ function.