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

Kessler, Nina; Viehmann, Susanne F.; Krollmann, Calvin; Mai, Karola; Kirschner, Katharina M.; Luksch, Hella; Kotagiri, Prasanti; Böhner, Alexander M. C.; Huugen, Dennis; Mann, Carina C. de Oliveira; Otten, Simon; Weiss, Stefanie A. I.; Zillinger, Thomas; Dobrikova, Kristiyana; Jenne, Dieter E.; Behrendt, Rayk; Ablasser, Andrea; Bartok, Eva; Hartmann, Gunther; Hopfner, Karl-Peter; Lyons, Paul A.; Boor, Peter; Rösen-Wolff, Angela; Teichmann, Lino L.; Heeringa, Peter; Kurts, Christian und Garbi, Natalio (2022): Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing. In: Journal of Experimental Medicine, Bd. 219, Nr. 10, e20220759

Abstract

Kessler 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 0022-1007
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 369799452
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390873048
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 272482170
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 264599542