Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome.

Autor: Konaka H; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.; Department of Internal Medicine, Nippon Life Hospital, Osaka, Japan., Kato Y; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.; Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan., Hirano T; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Nishinomiya Municipal Central Hospital, Nishinomiya, Japan., Tsujimoto K; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.; Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan., Park J; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Internal Medicine, Daini Osaka Police Hospital, Osaka, Japan., Koba T; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan., Aoki W; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan., Matsuzaki Y; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan., Taki M; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan., Koyama S; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan., Itotagawa E; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan., Jo T; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan., Hirayama T; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan., Kawai T; Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), Ikoma, Japan., Ishii KJ; Division of Vaccine Science, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Ueda M; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan., Yamaguchi S; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan., Akira S; Laboratory of Host Defense, Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan., Morita T; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan., Maeda Y; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan., Nishide M; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan., Nishida S; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan., Shima Y; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Division of Thermo-Therapeutics for Vascular Dysfunction, Graduate School of Medicine, Osaka University, Osaka, Japan., Narazaki M; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan., Takamatsu H; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.; Department of Clinical Research Center, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan., Kumanogoh A; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.; Department of Immunopathology, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.; Center for Infectious Disease for Education and Research (CiDER), Osaka University, Osaka, Japan.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2023 Oct 16; Vol. 42 (20), pp. e112573. Date of Electronic Publication: 2023 Sep 04.
DOI: 10.15252/embj.2022112573
Abstrakt: Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.
(© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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