Kessler, NinaViehmann, Susanne F.Krollmann, CalvinMai, KarolaKirschner, Katharina M.Luksch, HellaKotagiri, PrasantiBoehner, Alexander M. C.Huugen, DennisMann, Carina C. de OliveiraOtten, SimonWeiss, Stefanie A., IZillinger, ThomasDobrikova, KristiyanaJenne, Dieter E.Behrendt, RaykAblasser, AndreaBartok, EvaHartmann, GuntherHopfner, Karl-PeterLyons, Paul A.Boor, PeterRoesen-Wolff, AngelaTeichmann, Lino L.Heeringa, PeterKurts, ChristianGarbi, Natalio2022-10-242022-10-242022-10-242022-08-2310.1084/jem.20220759https://infoscience.epfl.ch/handle/20.500.14299/191640WOS:000862391200001Kessler et al. identify aberrant DNA recognition by cGAS/STING and IFN-I production by inflammatory macrophages as a driver of severe ANCA-associated vasculitis. Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery, identifying potential targets for therapeutic intervention in patients.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-beta, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-beta-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.ImmunologyMedicine, Research & ExperimentalResearch & Experimental Medicinecyclic gmp-ampdendritic cellscytosolic dnai interferonmitochondrial-dnasting activationcgasglomerulonephritismyeloperoxidaseneutrophilstext::journal::journal article::research article