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.

抗中性粒细胞胞浆抗体（ANCA）相关血管炎（AAV）的特征是在存在致病性ANCA的情况下坏死性血管炎。ANCA可能会引起嗜中性粒细胞活化并诱导嗜中性粒细胞胞外陷阱（NETs），从而导致内皮损伤以及自身反应性B细胞和替代补体途径的活化。重组血栓调节蛋白（rTM）在弥散性血管内凝血过程中保护内皮免受血管损伤，因此我们假设rTM可以改善AAV中的坏死性血管炎。在这项研究中，在实验性AAV大鼠模型中施用了rTM。用rTM治疗实验性AAV大鼠可改善肺出血和肾小球肾炎，并抑制ANCA产生和NETs形成。此外，体外实验表明，rTM通过Mac-1（巨噬细胞1抗原）与嗜中性粒细胞结合，并抑制ANCA诱导的NETs形成，同时抑制组蛋白瓜氨酸化，从而保护内皮免受NETs毒性的影响。另外，rTM影响的淋巴细胞导致在抗体生产过程中PBMC中促炎性细胞因子/趋化因子的抑制，这可能间接参与了病原性ANCA的减少。我们的数据表明，rTM可以通过多种生物学机制的结合来改善自身免疫性血管炎。