| Title: |
Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells induce Tfh differentiation 2062 |
| Authors: |
Xian, Hongxu; Ohira, Masafumi; Watari, Kosuke; Zuniga, Elina; Hoffman, Hal; Karin, Michael |
| Source: |
The Journal of Immunology ; volume 214, issue Supplement_1 ; ISSN 0022-1767 1550-6606 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2025 |
| Description: |
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) |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/jimmun/vkaf283.028 |
| Availability: |
https://doi.org/10.1093/jimmun/vkaf283.028; https://academic.oup.com/jimmunol/article-pdf/214/Supplement_1/vkaf283.028/65413199/vkaf283.028.pdf |
| Rights: |
https://academic.oup.com/pages/standard-publication-reuse-rights |
| Accession Number: |
edsbas.8C5CC62E |
| Database: |
BASE |