Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.
Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.
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DOI：
10.1172/jci159498
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发表时间：
2023-02-15
影响因子：
15.9
通讯作者：
Tian, Rong
中科院分区：
文献类型：
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作者：
Cai, Shanshan;Zhao, Mingyue;Zhou, Bo;Yoshii, Akira;Bugg, Darrian;Villet, Outi;Sahu, Anita;Olson, Gregory S;Davis, Jennifer;Tian, Rong
天然免疫细胞在急性心肌梗死(MI)后的组织损伤和修复中发挥重要作用。虽然在炎症和消退阶段观察到了巨噬细胞代谢的重新编程，但其与巨噬细胞表型的机制联系尚不完全清楚。在这项研究中，我们发现由Ndufs4编码的线粒体复合体I蛋白的髓系特异性缺失(MKO)重现了巨噬细胞的促炎代谢特征，并夸大了对内毒素的反应。此外，MKO小鼠在心肌梗死后30天表现出死亡率增加，疤痕形成不良，心功能恶化。我们观察到MKO小鼠在心肌梗死后第1天有较强的炎症反应，随后浸润的巨噬细胞死亡增加，并在3-7天钝化过渡到修复期。MKO巨噬细胞的效应细胞吞噬功能受损，导致抗炎细胞因子和组织修复因子的表达降低，从而抑制了梗死区肌成纤维细胞的增殖和激活。线粒体靶向的ROS清除挽救了这些损伤，改善了体内的肌成纤维细胞功能，并降低了MKO小鼠的心肌梗死后死亡率。综上所述，这些结果揭示了线粒体在炎症消退和组织修复中的关键作用，它通过调节胞吐作用和与成纤维细胞的串扰来实现。这些发现对心肌梗死后的恢复以及其他炎症情况都有潜在的意义。
Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3–7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.