Associate Investigator Versiti Blood Res. Inst., United States
Disclosure(s):
Hongxu Xian, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
