Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages.
Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages.
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DOI：
10.1016/j.cell.2017.08.041
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发表时间：
2017-10-05
期刊：
影响因子：
64.5
通讯作者：
Tabas I
中科院分区：
文献类型：
--
作者：
Wang Y;Subramanian M;Yurdagul A Jr;Barbosa-Lorenzi VC;Cai B;de Juan-Sanz J;Ryan TA;Nomura M;Maxfield FR;Tabas I
吞噬细胞对凋亡细胞（ACs）的清除（胞葬作用）可防止凋亡后坏死并抑制炎症。胞葬作用缺陷会引发包括动脉粥样硬化在内的重要疾病。为了实现有效的胞葬作用，吞噬细胞必须能够内化多个凋亡细胞。我们在此表明，巨噬细胞对多个凋亡细胞的摄取需要动力相关蛋白1（Drp1）介导的线粒体分裂，这是由凋亡细胞摄取所触发的。当线粒体分裂受阻时，由于线粒体对钙的螯合，凋亡细胞诱导的胞质钙增加会减弱，并且在后续遇到的凋亡细胞周围依赖钙的吞噬体形成会受损。这些缺陷可通过沉默线粒体钙单向转运体（MCU）来纠正。缺乏髓系Drp1的小鼠在地塞米松处理后的胸腺以及在高脂喂养的Ldlr - / - 小鼠的晚期动脉粥样硬化病变中表现出胞葬作用缺陷及其病理后果。因此，响应凋亡细胞摄取的线粒体分裂是一个关键过程，它使巨噬细胞能够清除多个凋亡细胞，并避免体内胞葬作用缺陷的病理后果。
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.
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非规范自噬抑制自身炎症，类似狼疮的对垂死细胞的反应。
影响因子：
64.8
作者：
Martinez J;Cunha LD;Park S;Yang M;Lu Q;Orchard R;Li QZ;Yan M;Janke L;Guy C;Linkermann A;Virgin HW;Green DR
通讯作者：
Green DR
影响因子：
64.8
作者：
Kojima Y;Volkmer JP;McKenna K;Civelek M;Lusis AJ;Miller CL;Direnzo D;Nanda V;Ye J;Connolly AJ;Schadt EE;Quertermous T;Betancur P;Maegdefessel L;Matic LP;Hedin U;Weissman IL;Leeper NJ
通讯作者：
Leeper NJ
影响因子：
7.2
作者：
Hochreiter-Hufford, Amelia;Ravichandran, Kodi S.
通讯作者：
Ravichandran, Kodi S.
DOI：
10.1253/circj.cj-16-0924
发表时间：
2016-10-25
期刊：
Circulation journal : official journal of the Japanese Circulation Society
影响因子：
--
作者：
Linton MF;Babaev VR;Huang J;Linton EF;Tao H;Yancey PG
通讯作者：
Yancey PG
影响因子：
10.8
作者：
Garbin, Ulisse;Baggio, Elda;Pasini, Anna Fratta
通讯作者：
Pasini, Anna Fratta