Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation 2253320

Abstract

Abstract Introduction The border between chronic inflammation and autoimmunity is obscure. It is unclear whether persistent innate immune activation breaches self-tolerance and initiates long-lasting autoimmune responses. A key danger signal that triggers sterile inflammation through NLRP3 inflammasome-mediated caspase-1 activation is Ox-mtDNA, an alarmin that enters the cytoplasm in response to mitochondrial stress. In addition to generating 8-oxo-deoxyguanosine (8-Oxo-dG)-containing DNA, which binds NLRP3, mtDNA oxidation promotes its cleavage into small fragments that pass through mitochondrial pores. Along with pro-IL-1β processing, activated Casp1 cleaves gasdermin-D to generate plasma membrane pores through which Ox-mtDNA escapes to the extracellular space and reaches the circulatory system. However, whether circulating Ox-mtDNA is simply a disease sign or an immunopathogenic driver, is unknown. It is also not clear whether and how mtDNA oxidation dictates its immunostimulatory activity. Methods pDC and CD4+ T cell co-culture Flow cytometry Histological evaluation and immunohistochemistry Immunofluorescence and confocal microscopy scRNA sequencing Results 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. Conclusion 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. Funding Source n/a Topic Categories Basic Autoimmunity (BA)