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Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH

Hongxu Xian1, Kosuke Watari1, Masafumi Ohira1

  • 1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA, USA.

Nature Immunology
|June 17, 2025
PubMed

Insights

Oxidized mitochondrial DNA (Ox-mtDNA) fragments trigger autoimmune diseases by activating immune cells. This study reveals Ox-mtDNA as a key driver of autoantibody production and glomerulonephritis, suggesting new therapeutic targets.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pathology

Background:

  • Oxidized mitochondrial DNA (Ox-mtDNA) fragments in the cytoplasm activate the NLRP3 inflammasome.
  • Elevated circulating mtDNA is observed in aging and in patients with metabolic or autoimmune disorders.

Purpose of the Study:

  • To investigate the role of sustained Ox-mtDNA release in inducing autoimmune responses.
  • To elucidate the mechanisms by which Ox-mtDNA triggers autoantibody production.

Main Methods:

  • Mice were treated with a NLRP3 inflammasome activator to induce sustained Ox-mtDNA release.
  • In vitro-generated Ox-mtDNA and non-oxidized mtDNA were used to assess immune cell activation.
  • Plasmacytoid dendritic cells (pDCs) and follicular helper T (TFH) cells were analyzed for their role in autoimmune responses.

Main Results:

  • Sustained Ox-mtDNA release induced autoantibody production and glomerulonephritis in mice.
  • Ox-mtDNA, but not non-oxidized mtDNA, elicited autoimmune responses dependent on pDCs and TFH cells.
  • Ox-mtDNA stimulated autocrine IL-1β signaling in pDCs, promoting TFH differentiation and autoantibody production.

Conclusions:

  • Oxidized mitochondrial DNA is a significant trigger for autoimmune diseases.
  • pDC-derived IL-1β plays a crucial role in autoantibody production.
  • Targeting Ox-mtDNA or IL-1β signaling may offer therapeutic strategies for autoimmune disorders.

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