Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
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DOI：
10.3389/fimmu.2023.1243548
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发表时间：
2023
影响因子：
7.3
通讯作者：
Kang, Young Jun
中科院分区：
文献类型：
--
作者：
Bang, Bo-Ram;Miki, Haruka;Kang, Young Jun
关键词：
巨噬细胞在炎症和组织稳态的调节中发挥着关键作用。除了对细胞生存和生理学的重要功能外，线粒体作为通过调节细胞信号传导和动力学诱导炎症反应的平台，在先天免疫中发挥着至关重要的作用。 Dynamin 相关蛋白 1 (Drp1) 在诱导炎症反应和各种疾病的后续发展中发挥作用。 PGAM5（磷酸甘油酸变位酶成员 5）是一种线粒体外膜磷酸酶，可使其底物 Drp1 去磷酸化。先前的研究表明，PGAM5 调节 Drp1 的磷酸化，从而激活 NKT 细胞和 T 细胞。然而，尚不清楚 PGAM5 如何调节 Drp1 活性以诱导巨噬细胞炎症。在这里，我们证明 PGAM5 活性调节巨噬细胞中 Drp1 的去磷酸化，从而诱导巨噬细胞中的促炎症反应。在TLR信号传导中，PGAM5通过调节下游信号通路（包括NF-κB和MAPK通路）的激活来调节炎症细胞因子的表达和产生。 LPS 刺激后，PGAM5 与 Drp1 相互作用形成复合物，从而产生 mtROS。此外，PGAM5-Drp1 信号传导促进巨噬细胞向促炎表型极化。我们的研究进一步表明，PGAM5-Drp1 信号通过上调巨噬细胞中的糖酵解和线粒体代谢来促进代谢重编程。总而言之，PGAM5 信号传导是 Drp1 介导的线粒体动力学变化与巨噬细胞炎症反应之间的联系，可能是治疗炎症性疾病的靶点。
Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling is a linker between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.
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影响因子：
7.3
作者：
Meyer A;Laverny G;Bernardi L;Charles AL;Alsaleh G;Pottecher J;Sibilia J;Geny B
通讯作者：
Geny B
DOI：
10.4049/jimmunol.1501662
发表时间：
2016-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Moriwaki K;Farias Luz N;Balaji S;De Rosa MJ;O'Donnell CL;Gough PJ;Bertin J;Welsh RM;Chan FK
通讯作者：
Chan FK
影响因子：
30.5
作者：
Matsuzawa, A;Saegusa, K;Ichijo, H
通讯作者：
Ichijo, H
影响因子：
4.8
作者：
Huang, Ying-ling;Morales-Rosado, Joel;Munford, Robert S.
通讯作者：
Munford, Robert S.
影响因子：
16.6
作者：
Kang YJ;Bang BR;Han KH;Hong L;Shim EJ;Ma J;Lerner RA;Otsuka M
通讯作者：
Otsuka M