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.
Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing
Disclosures: S.F. Viehmann started a job at AstraZeneca GmbH in the respiratory and immunology department after writing the original draft. At this time, research contributions submitted for publication were completed. R. Behrendt reported grants from Hoffmann-La Roche, ISD Immunotech, and IFM Therapeutics outside the submitted work. A. Ablasser is a co-founder of IFM-Due. P.A. Lyons reported grants from Medical Research Council during the conduct of the study; and holds founding equity in and consult for PredictImmune Ltd. No other disclosures were reported.
D. Huugen’s present address is Department of Internal Medicine, Deventer Hospital, Deventer, Netherlands.
- Award Id(s): 369799452,390873048,322900939,454024652,432698239,445703531,272482170,264599542,432325352,397484323,386793560,21637201,471514137,387333827,216372545
- Award Id(s): 668036 “RELENT”
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Nina Kessler, Susanne F. Viehmann, Calvin Krollmann, Karola Mai, Katharina M. Kirschner, Hella Luksch, Prasanti Kotagiri, Alexander M.C. Böhner, Dennis Huugen, Carina C. de Oliveira Mann, Simon Otten, Stefanie A.I. Weiss, Thomas Zillinger, Kristiyana Dobrikova, Dieter E. Jenne, Rayk Behrendt, Andrea Ablasser, Eva Bartok, Gunther Hartmann, Karl-Peter Hopfner, Paul A. Lyons, Peter Boor, Angela Rösen-Wolff, Lino L. Teichmann, Peter Heeringa, Christian Kurts, Natalio Garbi; Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing. J Exp Med 3 October 2022; 219 (10): e20220759. doi: https://doi.org/10.1084/jem.20220759
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