Thrombospondin-1 inhibits alternative complement pathway activation in vasculitis synergistically to factor H

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

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 von Willebrand factor (vWF). However, direct regulatory interaction with the complement cascade has not yet been described. We could show that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins, inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. Complement-regulatory function is validated in blood samples from patients with primary complement defects. Physiological relevance of TSP-1 is demonstrated in ANCA-vasculitis patients by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis following TSP-1 deficiency in an ANCA-vasculitis model. The newly described complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia, complement and platelets. In particular, the interplay between released TSP-1, vWF 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 16

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

2. Sophie Schroda

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

3. 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

4. Eva L. Decker

   University of Freiburg

   Affiliation as printed

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

5. Martin Pohl

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

6. 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, 79098 Freiburg, Germany

7. 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 Pauwelsstrasse 30, 52074, Aachen, Germany

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

8. Hong Wang

   University of Freiburg

   Affiliation as printed

   Centre for Integrative Biological Signalling Studies-CIBSS, University of Freiburg, 79104 Freiburg, Germany

   Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, 79104 Freiburg, Germany

9. Robert Grosse

   University of Freiburg

   Affiliation as printed

   Centre for Integrative Biological Signalling Studies-CIBSS, University of Freiburg, 79104 Freiburg, Germany

   Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, 79104 Freiburg, Germany

10. Manuel Rogg

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Institute of Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany

11. Christoph Schell

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, 79106 Freiburg, Germany

    Institute of Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany

12. Sabine Vidal

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

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

13. Xiaobo Liu

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

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

14. Christian Gorzelanny

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

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

15. 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

16. Karsten Häffner corresponding

    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