Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection
Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection
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DOI：
10.1016/j.jaut.2019.102390
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发表时间：
2020-03-01
影响因子：
12.8
通讯作者：
Ishizu, Akihiro
中科院分区：
文献类型：
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作者：
Watanabe-Kusunoki, Kanako;Nakazawa, Daigo;Ishizu, Akihiro
抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）的特征是坏死性血管炎伴病原性ANCA的存在。ANCA可潜在地引起中性粒细胞活化并诱导中性粒细胞胞外陷阱（NETs），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血管内皮免受血管损伤，因此我们假设rTM改善AAV中的坏死性血管炎。在本研究中，在实验性AAV大鼠模型中施用rTM。用rTM治疗实验性AAV大鼠改善了肺出血和肾小球肾炎，抑制了ANCA的产生和NET的形成。此外，体外实验表明，rTM通过Mac-1（巨噬细胞-1抗原）与中性粒细胞结合，并抑制ANCA诱导的NET形成，同时抑制组蛋白瓜氨酸，从而保护内皮免受NET毒性。此外，rTM影响淋巴细胞，导致抗体产生过程中PBMC中促炎细胞因子/趋化因子的抑制，这可能间接参与致病性ANCA的减少。我们的数据显示，rTM可以通过不同的生物学机制的组合来改善自身免疫性血管炎。
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.