Thrombospondin-1 inhibits alternative complement pathway activation in antineutrophil cytoplasmic antibody-associated vasculitis

Journal of Clinical Investigation, vol. 135

Abstract

Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement, and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and vWF. However, to our knowledge, direct regulatory interaction with the complement cascade has not yet been described. Our study shows that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins and inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. We validated complement-regulatory function in blood samples from patients with primary complement defects. The physiological relevance of TSP-1 was demonstrated in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis after TSP-1 deficiency in an in vitro and in vivo model of AAV. The complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.

Authors 15

1. Swagata Konwar

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of, University of Freiburg, Freiburg, Germany

2. Sophie Schroda

   University of Freiburg

   Affiliation as printed

   Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, and

   Department of General Pediatrics, Adolescent Medicine and Neonatology, Medi, University of Freiburg, Freiburg, Germany

3. Manuel Rogg

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany

   Institute of Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

4. Jessika Kleindienst

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of, University of Freiburg, Freiburg, Germany

5. Eva L. Decker

   University of Freiburg

   Affiliation as printed

   Plant Biotechnology, Faculty of Biology, University of Freiburg, Freiburg, Germany

6. Martin Pöhl

   University of Freiburg

   Affiliation as printed

   Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, and

   Department of General Pediatrics, Adolescent Medicine and Neonatology, Medi, University of Freiburg, Freiburg, Germany

7. Barbara Zieger

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany

   Division of Pediatric Hematology and Oncology, Department of Pediatrics and, Medical Center-University of Freiburg, Freiburg, Germany

8. Jens Panse Aachen Department of Oncology, Hematology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Center for Integrated Oncology (CIO), Aachen, Bonn, Cologne, Düsseldorf (ABCD) Germany, Aachen, Germany

   Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany

   Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplant, University Hospital RWTH Aachen, Aachen, Germany

9. Hong Wang

   University of Freiburg

   Affiliation as printed

   Centre for Integrative Biological Signalling Studies-CIBSS, and

   Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty,

   Institute of Experimental and Clinical Pharmacology and Toxicology, Medical, University of Freiburg, Freiburg, Germany

10. Robert Grosse

    University of Freiburg

    Affiliation as printed

    Centre for Integrative Biological Signalling Studies-CIBSS, and

    Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty,

    Institute of Experimental and Clinical Pharmacology and Toxicology, Medical, University of Freiburg, Freiburg, Germany

11. Christoph Schell

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany

    Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany

    Institute of Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

12. Xiaobo Liu

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

13. Christian Gorzelanny

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

14. Todor Tschongov

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of, University of Freiburg, Freiburg, Germany

15. Karsten Häffner

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of, University of Freiburg, Freiburg, Germany