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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Nina Kessler - , University of Bonn Medical Center (Author)
  • Susanne F Viehmann - , University of Bonn Medical Center (Author)
  • Calvin Krollmann - , University of Bonn Medical Center (Author)
  • Karola Mai - , University of Bonn Medical Center (Author)
  • Katharina M Kirschner - , University of Bonn Medical Center (Author)
  • Hella Luksch - , Department of Paediatrics, Technische Universität Dresden (Author)
  • Prasanti Kotagiri - , University of Cambridge (Author)
  • Alexander M C Böhner - , University of Bonn Medical Center (Author)
  • Dennis Huugen - , Maastricht University (Author)
  • Carina C de Oliveira Mann - , Ludwig Maximilian University of Munich (Author)
  • Simon Otten - , University Hospital Aachen (Author)
  • Stefanie A I Weiss - , Helmholtz Zentrum München - German Research Center for Environmental Health, Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Thomas Zillinger - , University of Bonn Medical Center (Author)
  • Kristiyana Dobrikova - , University of Bonn Medical Center (Author)
  • Dieter E Jenne - , Hospital of the Ludwig-Maximilians-University (LMU) Munich, Helmholtz Zentrum München - German Research Center for Environmental Health (Author)
  • Rayk Behrendt - , University of Bonn Medical Center (Author)
  • Andrea Ablasser - , Amsterdam Institute for Global Health and Development (Author)
  • Eva Bartok - , University of Bonn Medical Center (Author)
  • Gunther Hartmann - , University of Bonn Medical Center (Author)
  • Karl-Peter Hopfner - , Ludwig Maximilian University of Munich (Author)
  • Paul A Lyons - , University of Cambridge (Author)
  • Peter Boor - , University Hospital Aachen (Author)
  • Angela Rösen-Wolff - , Department of Paediatrics, Technische Universität Dresden (Author)
  • Lino L Teichmann - , University of Bonn Medical Center (Author)
  • Peter Heeringa - , University of Groningen (Author)
  • Christian Kurts - , University of Bonn Medical Center (Author)
  • Natalio Garbi - , University of Bonn Medical Center (Author)

Abstract

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.

Details

Original languageEnglish
Article numbere20220759
JournalThe Journal of experimental medicine
Volume219
Issue number10
Publication statusPublished - 3 Oct 2022
Peer-reviewedYes

External IDs

PubMedCentral PMC9402992
Scopus 85137123988
WOS 000862391200001

Keywords

Keywords

  • Animals, Interferon Type I, Lung, Macrophages, Membrane Proteins/metabolism, Mice, Nucleic Acids, Nucleotidyltransferases, Vasculitis, Sting activation, Glomerulonephritis, Dendritic cells, Neutrophils, I interferon, Cgas, Myeloperoxidase, Mitochondrial-dna, Cyclic gmp-amp, Cytosolic dna

Library keywords