The Mitochondrial Fission Regulator DRP1 Controls Post-Transcriptional Regulation of TNF-α

Frontiers in Cellular and Infection Microbiology

Jonathan Z. Sexton¹  Mack B. Reynolds²  Karla D. Passalacqua²  Basel H. Abuaita²  Mary X. D. O’Riordan²  Fushan Gao³ 

[1] Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, United States;U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, United States;Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI, United States;Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States;Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States;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;

关键词: mitochondria;    inflammation;    macrophage;    cellular stress;    cytokine;   

DOI  :  10.3389/fcimb.2020.593805

来源: Frontiers

【 摘 要 】

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 Staphylococcus aureus (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.

【 授权许可】

CC BY