Xian Hongxu, Watari Kosuke, Ohira Masafumi, Brito Jonathan S, He Peng, Onyuru Janset, Zuniga Elina I, Hoffman Hal M, Karin Michael
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA, USA.
Division of Pediatric Allergy, Immunology, and Rheumatology, Rady Children's Hospital of San Diego, University of California, San Diego, San Diego, CA, USA.
Nat Immunol. 2025 Jun 17. doi: 10.1038/s41590-025-02179-7.
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) 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 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.
应激诱导的氧化线粒体DNA（Ox-mtDNA）片段进入细胞质，激活NLRP3炎性小体和半胱天冬酶-1，并使gasdermin-D介导的mtDNA循环释放。在老年人以及患有代谢或自身免疫性疾病的患者中，已检测到循环中mtDNA的量升高，推测为氧化型。在此，我们表明，由典型的NLRP3炎性小体激活剂触发的持续Ox-mtDNA释放，可诱导小鼠产生自身抗体并引发肾小球肾炎。体外产生的Ox-mtDNA可引发类似的自身免疫反应，该反应依赖于浆细胞样树突状细胞（pDC）和滤泡辅助性T（T）细胞，但非氧化型mtDNA则不会引发此类反应。尽管两种mtDNA形式均被pDC内化并诱导干扰素-α，但只有Ox-mtDNA刺激自分泌白细胞介素（IL）-1β信号传导，从而诱导共刺激分子和IL-21，使小鼠和人类pDC能够诱导功能性T细胞分化，支持自身抗体的产生。这些发现强调了pDC产生的IL-1β在自身抗体产生中的作用，并突出了Ox-mtDNA作为重要的自身免疫触发因素，提示了潜在的治疗机会。
