Journal Article

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

Decker, Eva L., Schroda, Sophie, Rogg, Manuel, Konwar, Swagata, Panse, Jens, Gorzelanny, Christian, Tschongov, Todor, Häffner, Karsten, Wang, Hong, Vidal, Sabine, Grosse, Robert, Kleindienst, Jessika, Pohl, Martin, Zieger, Barbara, Liu, Xiaobo, Schell, Christoph

2025

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Anemia / Animals / Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - genetics / Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology / Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - metabolism / Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - pathology / Antibodies / Antineutrophil cytoplasmic antibodies / Blood platelets / Complement activation / Complement C3 - genetics / Complement C3 - immunology / Complement C3 - metabolism / Complement C5 - genetics / Complement C5 - immunology / Complement C5 - metabolism / Complement Factor H - genetics / Complement Factor H - immunology / Complement Factor H - metabolism / Complement Pathway, Alternative / Complement system / Endothelial cells / Endothelium / Female / Glycoproteins / Health aspects / Humans / Immunology / Inflammation / Investigations / Male / Membrane attack complex / Mice / Mice, Knockout / Middle Aged / Mutation / Physiological aspects / Platelets / Proteins / Regulation / Thrombospondin / Thrombospondin 1 - genetics / Thrombospondin 1 - immunology / Thrombospondin 1 - metabolism / Vascular biology / Vascular diseases / Vasculitis / Viral antibodies / Wound healing