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

Author:

Kessler Nina1ORCID,Viehmann Susanne F.1ORCID,Krollmann Calvin2ORCID,Mai Karola1ORCID,Kirschner Katharina M.1ORCID,Luksch Hella3ORCID,Kotagiri Prasanti4ORCID,Böhner Alexander M.C.15ORCID,Huugen Dennis6ORCID,de Oliveira Mann Carina C.7ORCID,Otten Simon8ORCID,Weiss Stefanie A.I.9ORCID,Zillinger Thomas10ORCID,Dobrikova Kristiyana1ORCID,Jenne Dieter E.911ORCID,Behrendt Rayk12ORCID,Ablasser Andrea13ORCID,Bartok Eva10ORCID,Hartmann Gunther10ORCID,Hopfner Karl-Peter7ORCID,Lyons Paul A.414ORCID,Boor Peter8ORCID,Rösen-Wolff Angela3ORCID,Teichmann Lino L.2ORCID,Heeringa Peter15ORCID,Kurts Christian1ORCID,Garbi Natalio1ORCID

Affiliation:

1. Institute of Molecular Medicine and Experimental Immunology, Medical Faculty, University of Bonn, Bonn, Germany 1

2. Medical Clinic and Polyclinic III, University Hospital Bonn, Bonn, Germany 2

3. Department of Pediatrics, Universitätsklinikum Carl Gustav Carus TU Dresden, Dresden, Germany 3

4. Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, UK 4

5. Department of Radiation Oncology, University Hospital Bonn, Bonn, Germany 6

6. Department of Internal Medicine, Division of Clinical and Experimental Immunology, University of Maastricht, Maastricht, Netherlands 7

7. Gene Center, Ludwig Maximilians University, Munich, Germany 8

8. Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany 9

9. Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig-Maximilians University, Munich, Germany 10

10. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany 11

11. Max Planck Institute of Neurobiology, Planegg-Martinsried, Planegg, Germany 12

12. Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany 13

13. Global Health Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland 14

14. Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK 5

15. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands 15

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.

Funder

Deutsche Forschungsgemeinschaft

European Union’s Horizon 2020

Cancer Research Institute

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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