TY - JOUR
T1 - Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages
AU - Wang, Ying
AU - Subramanian, Manikandan
AU - Yurdagul, Arif
AU - Barbosa-Lorenzi, Valéria C.
AU - Cai, Bishuang
AU - de Juan-Sanz, Jaime
AU - Ryan, Timothy A.
AU - Nomura, Masatoshi
AU - Maxfield, Frederick R.
AU - Tabas, Ira
N1 - Funding Information:
We wish to thank Dr. Toren Finkel (NIH) for providing the Mcu −/− mice, Drs. Mohammad Islam and Jahar Bhattacharya for assistance with the MCU experiments, George Kuriakose for technical contributions related to the atherosclerosis studies, Xiaobo Wang for assistance with isolation of aortic smooth muscle cells, the Herbert Irving Comprehensive Cancer Center Confocal Core Facility and Theresa Swayne and Laura Munteanu for assistance with confocal imaging, and the Columbia Center for Translational Immunology Core Facility for access to flow cytometry equipment (funded in part by NIH/NIDDK Center Grant 5P30DK063608 and by the Office of the NIH Director under Shared Instrumentation Grant S10OD020056 ). This study was supported by American Heart Association pre-doctoral training grant 11PRE7450075 (Y.W.); American Heart Association Post-Doctoral Fellowship grant 15POST25620024 (B.C.); KAKENHI grant 17K09885 from the Japanese Society for the Promotion of Science (M.N.); and NIH grants T32 HL007343-28 (A.Y.), R37 NS036942 (T.A.R.), R01 HL093324 (F.R.M.), and R01 HL075662 , HL127464 , and HL132412 (I.T.).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/10/5
Y1 - 2017/10/5
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2017.08.041
DO - 10.1016/j.cell.2017.08.041
M3 - Article
C2 - 28942921
AN - SCOPUS:85029682530
SN - 0092-8674
VL - 171
SP - 331-345.e22
JO - Cell
JF - Cell
IS - 2
ER -