Clearance of apoptotic cells (ACs) by phagocytes (efferocytosis) prevents post-apoptotic necrosis and dampens inflammation. Defective efferocytosis drives important diseases, including atherosclerosis. For efficient efferocytosis, phagocytes must be able to internalize multiple ACs. We show here that uptake of multiple ACs by macrophages requires dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which is triggered by AC uptake. When mitochondrial fission is disabled, AC-induced increase in cytosolic calcium is blunted owing to mitochondrial calcium sequestration, and calcium-dependent phagosome formation around secondarily encountered ACs is impaired. These defects can be corrected by silencing the mitochondrial calcium uniporter (MCU). Mice lacking myeloid Drp1 showed defective efferocytosis and its pathologic consequences in the thymus after dexamethasone treatment and in advanced atherosclerotic lesions in fat-fed Ldlr^-/- mice. Thus, mitochondrial fission in response to AC uptake is a critical process that enables macrophages to clear multiple ACs and to avoid the pathologic consequences of defective efferocytosis in vivo.

中文翻译：

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线粒体裂变促进巨噬细胞对凋亡细胞的持续清除。

吞噬细胞清除细胞凋亡（促红细胞增多症）可防止凋亡后坏死并减轻炎症。缺陷性红细胞增多症可驱动包括动脉粥样硬化在内的重要疾病。为了有效地进行胞吞作用，吞噬细胞必须能够内化多个AC。我们在这里显示巨噬细胞对多种AC的吸收需要动力相关的蛋白1（Drp1）介导的线粒体裂变，这是由AC吸收触发的。当线粒体裂变被禁用时，由于线粒体钙的螯合，AC诱导的胞质钙增加被抑制，并且继发于AC周围的钙依赖性吞噬体形成受到损害。可以通过沉默线粒体钙单向转运蛋白（MCU）来纠正这些缺陷。^-/-老鼠。因此，响应AC摄取的线粒体裂变是关键过程，其使巨噬细胞能够清除多个AC并避免体内缺陷性红细胞增多症的病理学后果。