Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages.
Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages.
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Stat2-Drp1 介导的线粒体质量增加对于巨噬细胞的促炎分化是必要的
DOI：
10.1016/j.redox.2020.101761
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发表时间：
2020-10
期刊：
影响因子：
11.4
通讯作者：
Hai C
中科院分区：
文献类型：
--
作者：
Yu W;Wang X;Zhao J;Liu R;Liu J;Wang Z;Peng J;Wu H;Zhang X;Long Z;Kong D;Li W;Hai C
巨噬细胞募集和促炎分化是包括感染和败血症在内的各种疾病的特征。虽然研究表明线粒体可能调节巨噬细胞的免疫反应，但目前尚不清楚线粒体质量是否影响巨噬细胞的促炎分化。在这里，我们发现脂多糖(LPS)激活的巨噬细胞比静止细胞具有更高的线粒体质量。因此，本研究旨在探讨线粒体质量增加在促炎分化巨噬细胞中的作用及其分子机制。结果表明，巨噬细胞线粒体质量的增加与炎性细胞因子的产生呈正相关。RNA-seq分析显示，内毒素可促进信号转导和转录激活因子2(Stat2)和动力蛋白相关蛋白1(Drp1)的表达，使线粒体正向分裂调控更为丰富。同时，基因敲除或药物抑制抑制了内毒素诱导的线粒体质量增加和促炎分化。此外，Stat2促进丝氨酸616处的Drp1磷酸化，这是Drp1介导的线粒体分裂所必需的。脂多糖还导致依赖Stat2和Drp1的生物发生，这有助于产生额外的线粒体。然而，这些线粒体被深刻地重塑，显示出碎裂的形态、疏松的嵴、减少的Δψm和代谢编程。此外，这些重塑的线粒体将其功能从三磷酸腺苷合成转移到活性氧自由基(ROS)的产生，从而驱动依赖于NFκB的炎性细胞因子的转录。有趣的是，在没有内毒素刺激的情况下，线粒体质量的增加与结构性活性的Drp1S616E磷酸化突变体(Drp1S616E)增强了巨噬细胞的促炎反应。在体内，我们还证明了Mdivi-1给药抑制了内毒素诱导的巨噬细胞促炎分化。重要的是，我们观察到从脂多糖攻击的小鼠分离的巨噬细胞中Stat2的磷酸化和依赖于Drp1的线粒体质量增加。综上所述，我们全面论证了依赖Stat2-Drp1的线粒体质量增加对于巨噬细胞的促炎分化是必要的。因此，靶向Stat2-Drp1轴可能为治疗感染和炎症性疾病提供新的治疗方法。Stat2-Drp1诱导的线粒体质量增加在促进巨噬细胞促炎分化中的关键作用示意图。内毒素激活的巨噬细胞通过诱导Stat2-Drp1依赖的线粒体分裂和生物发生而拥有更多的线粒体。然而，这些线粒体经历了深刻的重塑，包括形态碎裂、嵴疏松、Δψm降低和代谢编程，导致从κ合成到ROS产生的功能转变，并进一步驱动依赖于NF-ATPB的炎性细胞因子的转录。巨噬细胞线粒体质量增加与炎性细胞因子相关。脂多糖增加线粒体分裂调节蛋白(Stat2和Drp1)的表达。Stat2和Drp1的增加有助于产生额外的线粒体。新的线粒体在形态上发生改变，并在代谢上重新编程。重新编程的线粒体从ATP合成转变为ROS产生。
Macrophage recruitment and pro-inflammatory differentiation are hallmarks of various diseases, including infection and sepsis. Although studies suggest that mitochondria may regulate macrophage immune responses, it remains unclear whether mitochondrial mass affects macrophage pro-inflammatory differentiation. Here, we found that lipopolysaccharide (LPS)-activated macrophages possess higher mitochondrial mass than resting cells. Therefore, this study aimed to explore the functional role and molecular mechanisms of increased mitochondrial mass in pro-inflammatory differentiated macrophages. Results show that an increase in the mitochondrial mass of macrophages positively correlates with inflammatory cytokine generation in response to LPS. RNA-seq analysis revealed that LPS promotes signal transducers and activators of transcription 2 (Stat2) and dynamin-related protein 1 (Drp1) expression, which are enriched in positive mitochondrial fission regulation. Meanwhile, knockdown or pharmacological inhibition of Drp1 blunts LPS-induced mitochondrial mass increase and pro-inflammatory differentiation. Moreover, Stat2 boosts Drp1 phosphorylation at serine 616, required for Drp1-mediated mitochondrial fission. LPS also causes Stat2-and Drp1-dependent biogenesis, which contributes to the generation of additional mitochondria. However, these mitochondria are profoundly remodeled, displaying fragmented morphology, loose cristae, reduced Δψm, and metabolic programming. Furthermore, these remodeled mitochondria shift their function from ATP synthesis to reactive oxygen species (ROS) production, which drives NFκB-dependent inflammatory cytokine transcription. Interestingly, an increase in mitochondrial mass with constitutively active phosphomimetic mutant of Drp1 (Drp1S616E) boosted pro-inflammatory response in macrophages without LPS stimulation. In vivo, we also demonstrated that Mdivi-1 administration inhibits LPS-induced macrophage pro-inflammatory differentiation. Importantly, we observed Stat2 phosphorylation and Drp1-dependent mitochondrial mass increase in macrophages isolated from LPS-challenged mice. In conclusion, we comprehensively demonstrate that a Stat2-Drp1 dependent mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages. Therefore, targeting the Stat2-Drp1 axis may provide novel therapeutic approaches for treating infection and inflammatory diseases. Schematic for the key role of Stat2-Drp1 induced mitochondrial mass increase in promoting pro-inflammatory differentiation of macrophages. LPS-activated macrophages possess more mitochondria by inducing Stat2-Drp1-dependent mitochondrial fission and biogenesis. However, these mitochondria undergo profound remodeling, including fragmented morphology, loose cristae, reduced Δψm, and metabolic programming, which induces a functional shift from ATP synthesis to ROS production, and further drives transcription of NFκB-dependent inflammatory cytokine production. Increased macrophage mitochondrial mass correlates with inflammatory cytokines. LPS increases mitochondrial fission regulatory protein (Stat2 and Drp1) expression. Increased Stat2 and Drp1 contribute to generation of additional mitochondria. New mitochondria are morphologically altered and metabolically reprogrammed. Reprogrammed mitochondria shift from ATP synthesis to ROS production.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
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
影响因子：
41.2
作者：
Jain N;Vogel V
通讯作者：
Vogel V
影响因子：
4.4
作者：
Indo, Hiroko P.;Davidson, Mercy;Majima, Hideyuki J.
通讯作者：
Majima, Hideyuki J.
影响因子：
7.3
作者：
Fontecha-Barriuso, Miguel;Martin-Sanchez, Diego;Sanz, Ana B.
通讯作者：
Sanz, Ana B.