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Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation. Nat Immunol 2025 Jul;26(7):1168-1181

Date

06/18/2025

Pubmed ID

40528028

DOI

10.1038/s41590-025-02179-7

Scopus ID

2-s2.0-105008250331 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

Stress-induced oxidized mitochondrial DNA (Ox-mtDNA) fragments enter the cytoplasm, activating the NLRP3 inflammasome and caspase-1 and enabling gasdermin-D-mediated circulatory release of mtDNA. Elevated amounts of circulating mtDNA, presumably oxidized, have been detected in older individuals and patients with metabolic or autoimmune disorders. Here we show that sustained Ox-mtDNA release, triggered by a prototypical NLRP3 inflammasome activator, induces autoantibody production and glomerulonephritis in mice. Similar autoimmune responses, dependent on plasmacytoid dendritic cells (pDCs) and follicular helper T (TFH) cells, are elicited by in vitro-generated Ox-mtDNA, but not by non-oxidized mtDNA. Although both mtDNA forms are internalized by pDCs and induce interferon-α, only Ox-mtDNA stimulates autocrine interleukin (IL)-1β signaling that induces co-stimulatory molecules and IL-21, which enable mouse and human pDCs to induce functional TFH differentiation, supportive of autoantibody production. These findings underscore the role of pDC-generated IL-1β in autoantibody production and highlight Ox-mtDNA as an important autoimmune trigger, suggesting potential therapeutic opportunities.

Author List

Xian H, Watari K, Ohira M, Brito JS, He P, Onyuru J, Zuniga EI, Hoffman HM, Karin M

Author

Hongxu Xian PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Autoantibodies
Autoimmunity
Cell Differentiation
Cells, Cultured
DNA, Mitochondrial
Dendritic Cells
Glomerulonephritis
Humans
Inflammasomes
Interleukin-1beta
Interleukins
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein
Oxidation-Reduction
Signal Transduction