Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome.
Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome.
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线粒体钙单转运体促进NLRP3炎症体的吞噬依赖激活。
DOI：
10.1073/pnas.2123247119
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发表时间：
2022-06-28
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Mitochondrial Ca2+ uniporter (MCU) has been recently reported to be involved in activation of the NLRP3 inflammasome due to mitochondrial damage. However, whether MCU is a general regulator of NLRP3 inflammasome and the overall effect of MCU on inflammation remain elusive. Here, we show that deletion of MCU causes no general defect in NLRP3 inflammasome activation. Instead, MCU is uniquely required for phagocytosis-triggered activation of NLRP3 inflammasome by counteracting ERCRT complex–mediated phagolysosomal membrane repair. Our data also suggest a proinflammatory effect of myeloid-derived MCU in an alum-induced peritonitis model. Therefore, our study provides genetic evidence to clarify the innate immune function of MCU. Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (McuΔmye) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1β release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1β release in McuΔmye macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in McuΔmye macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, McuΔmye mice showed a pronounced decrease in immune cell recruitment and IL-1β production in alum-induced peritonitis, a typical IL-1–dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
32.4
作者：
Iyer SS;He Q;Janczy JR;Elliott EI;Zhong Z;Olivier AK;Sadler JJ;Knepper-Adrian V;Han R;Qiao L;Eisenbarth SC;Nauseef WM;Cassel SL;Sutterwala FS
通讯作者：
Sutterwala FS
影响因子：
28.3
作者：
Li T;Kong L;Li X;Wu S;Attri KS;Li Y;Gong W;Zhao B;Li L;Herring LE;Asara JM;Xu L;Luo X;Lei YL;Ma Q;Seveau S;Gunn JS;Cheng X;Singh PK;Green DR;Wang H;Wen H
通讯作者：
Wen H
影响因子：
8.8
作者：
Kwong JQ;Lu X;Correll RN;Schwanekamp JA;Vagnozzi RJ;Sargent MA;York AJ;Zhang J;Bers DM;Molkentin JD
通讯作者：
Molkentin JD
DOI：
10.1073/pnas.1210718109
发表时间：
2012-08-07
影响因子：
11.1
作者：
Drago, Ilaria;De Stefani, Diego;Pozzan, Tullio
通讯作者：
Pozzan, Tullio