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

  • J Exp Med. 2022 Oct 3;219(10):e20220759. doi: 10.1084/jem.20220759.
Nina Kessler  #  1 ,  Susanne F Viehmann  #  1 ,  Calvin Krollmann  2 ,  Karola Mai  1 ,  Katharina M Kirschner  1 ,  Hella Luksch  3 ,  Prasanti Kotagiri  4 ,  Alexander M C Böhner  1  5 ,  Dennis Huugen  6 ,  Carina C de Oliveira Mann  7 ,  Simon Otten  8 ,  Stefanie A I Weiss  9 ,  Thomas Zillinger  10 ,  Kristiyana Dobrikova  1 ,  Dieter E Jenne  9  11 ,  Rayk Behrendt  12 ,  Andrea Ablasser  13 ,  Eva Bartok  10 ,  Gunther Hartmann  10 ,  Karl-Peter Hopfner  7 ,  Paul A Lyons  4  14 ,  Peter Boor  8 ,  Angela Rösen-Wolff  3 ,  Lino L Teichmann  2 ,  Peter Heeringa  #  15 ,  Christian Kurts  #  1 ,  Natalio Garbi  #  1
Affiliations
  • 1. Institute of Molecular Medicine and Experimental Immunology, Medical Faculty, University of Bonn, Bonn, Germany.
  • 2. Medical Clinic and Polyclinic III, University Hospital Bonn, Bonn, Germany.
  • 3. Department of Pediatrics, Universitätsklinikum Carl Gustav Carus TU Dresden, Dresden, Germany.
  • 4. Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • 5. Department of Radiation Oncology, University Hospital Bonn, Bonn, Germany.
  • 6. Department of Internal Medicine, Division of Clinical and Experimental Immunology, University of Maastricht, Maastricht, Netherlands.
  • 7. Gene Center, Ludwig Maximilians University, Munich, Germany.
  • 8. Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
  • 9. Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig-Maximilians University, Munich, Germany.
  • 10. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
  • 11. Max Planck Institute of Neurobiology, Planegg-Martinsried, Planegg, Germany.
  • 12. Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
  • 13. Global Health Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland.
  • 14. Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
  • 15. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
  • # Contributed equally.
PMID: 35997679 DOI: 10.1084/jem.20220759
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.

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