Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis.
Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis.
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DOI：
10.1136/annrheumdis-2016-210706
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发表时间：
2017-08
影响因子：
27.4
通讯作者：
Kumanogoh A
中科院分区：
文献类型：
--
作者：
Nishide M;Nojima S;Ito D;Takamatsu H;Koyama S;Kang S;Kimura T;Morimoto K;Hosokawa T;Hayama Y;Kinehara Y;Kato Y;Nakatani T;Nakanishi Y;Tsuda T;Park JH;Hirano T;Shima Y;Narazaki M;Morii E;Kumanogoh A
中性粒细胞的不适当激活在抗神经细胞胞浆抗体（ANCA）相关性血管炎（AAV）中起病理作用。本研究旨在探讨脑信号蛋白4D（semaphorin 4D，SEMA 4D）在调节中性粒细胞活化中的作用及其在AAV发病机制中的作用。通过ELISA评估可溶性SEMA 4D的血清水平。通过流式细胞术评估膜SEMA 4D的血细胞表面表达。为了确定中性粒细胞膜SEMA 4D和内皮丛蛋白B2之间的功能相互作用，将野生型和SEMA 4D −/−小鼠中性粒细胞与SYTOX绿色染色的内皮细胞系（MS 1）一起培养，并进行中性粒细胞胞外陷阱（NET）形成试验。通过测量动力学氧化爆发和NET形成测定来评估用重组丛蛋白B2治疗人中性粒细胞的功效。可溶性SEMA 4D的血清水平在AAV患者中升高，并且与疾病活动性评分相关。细胞表面SEMA 4D的表达下调，从AAV患者的中性粒细胞，膜SEMA 4D的蛋白水解裂解的结果。可溶性SEMA 4D对内皮细胞产生促炎作用。中性粒细胞上的膜SEMA 4D与内皮细胞上的丛蛋白B2结合，这种相互作用减少了NET的形成。重组丛蛋白B2通过SEMA 4D的胞内结构域抑制中性粒细胞Rac 1活化，并抑制病原体诱导或ANCA诱导的氧化爆发和NET形成。中性粒细胞表面SEMA 4D作为中性粒细胞活化的负调节剂起作用。在AAV患者中观察到的SEMA 4D的蛋白水解裂解可能放大嗜中性粒细胞介导的炎症反应。SEMA 4D是一种很有前途的AAV生物标志物和潜在的治疗靶点。
Inappropriate activation of neutrophils plays a pathological role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to investigate the functions of semaphorin 4D (SEMA4D) in regulation of neutrophil activation, and its involvement in AAV pathogenesis. Serum levels of soluble SEMA4D were evaluated by ELISA. Blood cell-surface expression of membrane SEMA4D was evaluated by flow cytometry. To determine the functional interactions between neutrophil membrane SEMA4D and endothelial plexin B2, wild-type and SEMA4D −/− mice neutrophils were cultured with an endothelial cell line (MS1) stained with SYTOX green, and subjected to neutrophil extracellular trap (NET) formation assays. The efficacy of treating human neutrophils with recombinant plexin B2 was assessed by measuring the kinetic oxidative burst and NET formation assays. Serum levels of soluble SEMA4D were elevated in patients with AAV and correlated with disease activity scores. Cell-surface expression of SEMA4D was downregulated in neutrophils from patients with AAV, a consequence of proteolytic cleavage of membrane SEMA4D. Soluble SEMA4D exerted pro-inflammatory effects on endothelial cells. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation. Recombinant plexin B2 suppressed neutrophil Rac1 activation through SEMA4D’s intracellular domain, and inhibited pathogen-induced or ANCA-induced oxidative burst and NET formation. Neutrophil surface SEMA4D functions as a negative regulator of neutrophil activation. Proteolytic cleavage of SEMA4D as observed in patients with AAV may amplify neutrophil-mediated inflammatory responses. SEMA4D is a promising biomarker and potential therapeutic target for AAV.
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影响因子：
82.9
作者：
Phillipson M;Kubes P
通讯作者：
Kubes P
影响因子：
4.4
作者：
Okuno, Tatsusada;Nakatsuji, Yuji;Kumanogoh, Atsushi
通讯作者：
Kumanogoh, Atsushi
影响因子：
20.3
作者：
Wang, XS;Kumanogoh, A;Kikutani, H
通讯作者：
Kikutani, H
影响因子：
5.4
作者：
Walcheck, B;Herrera, AH;DeLeo, FR
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DeLeo, FR
影响因子：
13.3
作者：
Yoshida, Yuji;Ogata, Atsushi;Kang, Sujin;Ebina, Kousuke;Shi, Kenrin;Nojima, Satoshi;Kimura, Tetsuya;Ito, Daisuke;Morimoto, Keiko;Nishide, Masayuki;Hosokawa, Takashi;Hirano, Toru;Shima, Yoshihito;Narazaki, Masashi;Tsuboi, Hideki;Saeki, Yukihiko;Tomita, Tetsuya;Tanaka, Toshio;Kumanogoh, Atsushi
通讯作者：
Kumanogoh, Atsushi