Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased levels of cGAMP and enhanced IFN-I signature. To identify disease mechanisms and potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-β, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-β-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I, or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcomes.
Details
Original language | English |
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Article number | e20220759 |
Journal | The Journal of experimental medicine |
Volume | 219 |
Issue number | 10 |
Publication status | Published - 3 Oct 2022 |
Peer-reviewed | Yes |
External IDs
PubMedCentral | PMC9402992 |
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Scopus | 85137123988 |
WOS | 000862391200001 |
Keywords
ASJC Scopus subject areas
Keywords
- Animals, Interferon Type I, Lung, Macrophages, Membrane Proteins/metabolism, Mice, Nucleic Acids, Nucleotidyltransferases, Vasculitis, Sting activation, Glomerulonephritis, Dendritic cells, Neutrophils, I interferon, Cgas, Myeloperoxidase, Mitochondrial-dna, Cyclic gmp-amp, Cytosolic dna