Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing vasculitis with the presence of pathogenic ANCA. ANCA can potentially cause neutrophil activation and induce neutrophil extracellular traps (NETs), resulting in endothelial damage as well as activation of autoreactive B cells and alternative complement pathway. Recombinant thrombomodulin (rTM) protects the endothelium from vascular injury during disseminated intravascular coagulation, thus we hypothesized that rTM ameliorates necrotizing vasculitis in AAV. In this study, rTM was administered in an experimental AAV rat model. Treatment of experimental AAV rats with rTM improved pulmonary hemorrhage and glomerulonephritis, with a suppression of ANCA production and NETs formation. In addition, in vitro experiments showed that rTM bound to neutrophils via Mac-1 (macrophage-1 antigen) and inhibited ANCA-induced NETs formation accompanied by a suppression of histone citrullination, leading to a protection of the endothelium from NETs toxicity. Additionally, rTM affected lymphocytes leading to the inhibition of pro-inflammatory cytokine/chemokin in PBMC during the antibody production process, which might indirectly be involved in the reduction of pathogenic ANCA. Our data revealed that the rTM could ameliorate autoimmune vasculitis through a combination of different biological mechanisms. •Recombinant thrombomodulin (rTM) in experimental vasculitis models ameliorated tissue injury with a suppression of NETs formation and autoantibody (ANCA).•rTM binds to neutrophils via Mac-1 receptor and suppresses NET signalling pathway, resulting in the protection of endothelial injury.•rTM affects lymphocytes leading to the inhibition of PBMCs with pro-inflammatory cytokine/chemokine profile.•Our data indicate that rTM functions beyond anti-coagulation as an immune-modulator, implying that rTM treatment could become a novel therapeutic target for autoimmune vasculitis.