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

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

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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