Circulating oxidized mitochondrial DNA drives autoimmunity

The innate immune system instructs adaptive immune activation to maintain host homeostasis, dysregulations of which underly many immune pathologies. Despite the multifold interactions, it is unclear whether innate immune responses are sufficient to enable adaptive activation and provoke disease. Breakdown of self-tolerance in T and B cells results in autoimmunity, yet innate immune control of self-reactivity is poorly understood. Mitochondrial DNA (mtDNA) recently has emerged in autoimmune disorders. However, it is unclear how mitochondrial stress associated with inflammation skews downstream aberrant adaptive responses. Here we show circulating cell-free (ccf-) oxidized (Ox-) mtDNA, induced during NLRP3 inflammasome activation, drives antibody mediated systematic autoimmunity. Abundant ccf-Ox-mtDNA in mice triggered by persistent peritonitis leads to SLE-like pathologies, development of which specifically relies on the oxidation of mtDNA. Although non-oxidized and Ox-mtDNA are both interferogenic to induce IFN-I signaling in pDCs, only Ox-mtDNA induces caspase-1 activation and IL-21 and IL-1β production, required for Tfh responses to support antibody production, leading to GC reactions and pathogenic antibodies deposition on kidney. This study establishes Ox-mtDNA ascribed by diverse chronic inflammatory diseases as a key to engage self-tolerance breach, highlights the innate immune origins of autoimmunity, and provides therapeutic targets for autoimmune disorders.