RRC ID 77507
Author Konaka H, Kato Y, Hirano T, Tsujimoto K, Park J, Koba T, Aoki W, Matsuzaki Y, Taki M, Koyama S, Itotagawa E, Jo T, Hirayama T, Kawai T, Ishii KJ, Ueda M, Yamaguchi S, Akira S, Morita T, Maeda Y, Nishide M, Nishida S, Shima Y, Narazaki M, Takamatsu H, Kumanogoh A.
Title Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome.
Journal EMBO J
Abstract 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.
Volume 42(20)
Pages e112573
Published 2023-10-16
DOI 10.15252/embj.2022112573
PMID 37661814
PMC PMC10577637
MeSH Behcet Syndrome* / genetics Behcet Syndrome* / metabolism Caspases / metabolism DNA, Mitochondrial / genetics DNA, Mitochondrial / metabolism Exosomes* / genetics Humans Inflammation / metabolism Mitochondria / genetics
IF 9.889
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384)