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<p>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 (T<sub>FH</sub>) 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 T<sub>FH</sub> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年6月17日

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  • Hongxu Xian,
  • Kosuke Watari,
  • Masafumi Ohira,
  • Jonathan S. Brito,
  • Peng He,
  • Janset Onyuru,
  • Elina I. Zuniga,
  • Hal M. Hoffman,
  • Michael Karin

摘要

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.