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Kessler, Nina; Viehmann, Susanne F.; Krollmann, Calvin; Mai, Karola; Kirschner, Katharina M.; Luksch, Hella; Kotagiri, Prasanti; Böhner, Alexander M.C.; Huugen, Dennis; de Oliveira Mann, Carina C.; 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.; [...]

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

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  • Medientyp: E-Artikel
  • Titel: Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing
  • Beteiligte: Kessler, Nina; Viehmann, Susanne F.; Krollmann, Calvin; Mai, Karola; Kirschner, Katharina M.; Luksch, Hella; Kotagiri, Prasanti; Böhner, Alexander M.C.; Huugen, Dennis; de Oliveira Mann, Carina C.; 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.; [...]
  • Erschienen: Rockefeller University Press, 2022
  • Erschienen in: Journal of Experimental Medicine
  • Sprache: Englisch
  • DOI: 10.1084/jem.20220759
  • ISSN: 1540-9538; 0022-1007
  • Schlagwörter: Immunology ; Immunology and Allergy
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>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.</jats:p>
  • Zugangsstatus: Freier Zugang