Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells induce Tfh differentiation 2062
Year: 2025
Type: article
Abstract: Description NLRP3 inflammasome activation depends on stress-induced production of oxidized mitochondrial DNA (Ox-mtDNA) fragments that enter the cytoplasm to bind NLRP3 and activate caspase-1. Along with pro-IL-1b processing, caspase-1 generates gasdermin D pores that result in circulatory mtDNA release. Elevated amounts of circulating cell-free (ccf)-mtDNA, which is likely to be oxidized, were documented in the elderly and patients with metabolic and autoimmune disorders and its intra-articular injection elicited arthritis in mice. Investigating whether ccf-mtDNA may promote autoimmunity, we found that induction of sustained Ox-mtDNA release triggered by a prototypical NLRP3 inflammasome activator elicited autoantibody production and glomerulonephritis in mice. Similar autoimmune responses, dependent on plasmacytoid dendritic cells (pDC) and T follicular helper cells (Tfh), were elicited by in-vitro generated Ox-mtDNA but not by non-oxidized mtDNA. Although both mtDNA forms were internalized by pDC and induced interferon-a, only Ox-mtDNA stimulated autocrine IL-1β signaling that induced expression of immunoregulatory and co-stimulatory molecules, including IL-21, that enabled mouse and human pDC convert naïve CD4+ T cells into functional Tfh, supportive of autoantibody production. Highlighting pDC-generated IL-1β as an orchestrator of autoantibody production, these findings suggest that Ox-mtDNA could be a key participant in immune-aging and unravel new therapeutic opportunities. Funding Sources Arthritis National Research Foundation (#1291101); NIH grants R01 DK100640 and R37 AI043477 Topic Categories Basic Autoimmunity (BA)
Source: The Journal of Immunology
Authors: Hongxu Xian, Masafumi Ohira, Kosuke Watari, Elina Zuniga, Hal Hoffman, Michael Karin
Institution: University of California San Diego
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416448946
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