Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.
Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China.
Front Cell Infect Microbiol. 2021 Jan 14;10:593805. doi: 10.3389/fcimb.2020.593805. eCollection 2020.
The mitochondrial network plays a critical role in the regulation of innate immune signaling and subsequent production of proinflammatory cytokines such as IFN-β and IL-1β. Dynamin-related protein 1 (DRP1) promotes mitochondrial fission and quality control to maintain cellular homeostasis during infection. However, mechanisms by which DRP1 and mitochondrial dynamics control innate immune signaling and the proinflammatory response are incompletely understood. Here we show that macrophage DRP1 is a positive regulator of TNF-α production during sterile inflammation or bacterial infection. Silencing macrophage DRP1 decreased mitochondrial fragmentation and TNF-α production upon stimulation with lipopolysaccharide (LPS) or methicillin-resistant (MRSA) infection. The defect in TNF-α induction could not be attributed to changes in gene expression. Instead, DRP1 was required for post-transcriptional control of TNF-α. In contrast, silencing DRP1 enhanced IL-6 and IL-1β production, indicating a distinct mechanism for DRP1-dependent TNF-α regulation. Our results highlight DRP1 as a key player in the macrophage pro-inflammatory response and point to its involvement in post-transcriptional control of TNF-α production.
线粒体网络在先天免疫信号的调节以及随后的促炎细胞因子（如 IFN-β 和 IL-1β）的产生中起着关键作用。与 dynamin 相关蛋白 1（DRP1）在感染期间促进线粒体裂变和质量控制，以维持细胞内稳态。然而，DRP1 和线粒体动力学控制先天免疫信号和促炎反应的机制尚不完全清楚。在这里，我们表明巨噬细胞 DRP1 是无菌炎症或细菌感染期间 TNF-α 产生的正调节剂。沉默巨噬细胞 DRP1 可减少 LPS 或耐甲氧西林金黄色葡萄球菌（MRSA）感染刺激时的线粒体碎片化和 TNF-α 产生。诱导 TNF-α 的缺陷不能归因于基因表达的变化。相反，DRP1 是 TNF-α 转录后控制所必需的。相比之下，沉默 DRP1 增强了 IL-6 和 IL-1β 的产生，表明 DRP1 依赖的 TNF-α 调节存在独特的机制。我们的研究结果突出了 DRP1 作为巨噬细胞促炎反应的关键参与者，并表明其参与了 TNF-α 产生的转录后控制。
