PuSH - Publikationsserver des Helmholtz Zentrums München: Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing.

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Kessler, N.* ; Viehmann, S.F.* ; Krollmann, C.* ; Mai, K.* ; Kirschner, K.M.* ; Luksch, H.* ; Kotagiri, P.* ; Böhner, A.M.C.* ; Huugen, D.* ; de Oliveira Mann, C.C.* ; Otten, S.* ; Weiss, S.A. ; Zillinger, T.* ; Dobrikova, K.* ; Jenne, D. ; Behrendt, R.* ; Ablasser, A.* ; Bartok, E.* ; Hartmann, G.* ; Hopfner, K.P.* ; Lyons, P.A.* ; Boor, P.* ; Rosen-Wolff, A.* ; Teichmann, L.L.* ; Heeringa, P.* ; Kurts, C.* ; Garbi, N.*

Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing.

J. Exp. Med. 219:e20220759 (2022)

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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.

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