School of Medical Technology, Xi'an Medical University, Xi'an, Shaanxi Province 710021, China.
Department of Clinical Laboratory, The Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710003, China.
Biomed Res Int. 2020 Dec 16;2020:6663291. doi: 10.1155/2020/6663291. eCollection 2020.
Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors-plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1, IL-6, and IL-8. The disintegrin and metalloproteinase domain 17- (AMAM17-) mediated Sema4D shedding from neutrophils contributed to the elevation of sSema4D in the serum of KD patients. Furthermore, we found that Sema4D induced IL-1 production of HCAECs via plexin B2, whereas it promoted IL-6 and IL-8 production via plexin B1. Moreover, the expression of both plexin B1 and plexin B2 was upregulated in HCAECs treated with KD sera, and silencing of the two plexin receptors suppressed the overexpression of IL-1, IL-6, and IL-8 in KD serum-treated HCAECs. Thus, our findings indicated that sSema4D released from neutrophils participates in the pathogenesis of KD-CALs by promoting inflammatory cytokine production of ECs via both plexin B1 and plexin B2, and Sema4D may be a novel predictor for KD-CALs and a candidate therapeutic target for anti-inflammatory strategies of KD.
内皮细胞（ECs）的炎症在川崎病（KD）冠状动脉病变（CALs）的发病机制中起着重要作用。Semaphorin 4D（Sema4D）是第一个通过与其受体 plexin Bs 相互作用显示出免疫调节功能的 semaphorin。最近，Sema4D 被报道对内皮细胞具有促炎作用，并参与心血管疾病。然而，Sema4D 在 KD 中的作用尚不清楚。本研究旨在揭示可溶性 Sema4D（sSema4D）在 KD 患者血清中的变化，以及 sSema4D-plexin 轴对 KD 患者血清刺激的人冠状动脉内皮细胞（HCAEC）产生促炎细胞因子的影响。我们的结果表明，血清 sSema4D 水平在 KD 患者中特异性升高，尤其是在有 CALs 的患者中，并且与疾病严重程度和血清白细胞介素（IL）-1、IL-6 和 IL-8 浓度呈正相关。中性粒细胞中 ADAM17 介导的 Sema4D 脱落导致 KD 患者血清中 sSema4D 升高。此外，我们发现 Sema4D 通过 plexin B2 诱导 HCAEC 产生 IL-1，而通过 plexin B1 促进 IL-6 和 IL-8 的产生。此外，KD 血清处理的 HCAEC 中 plexin B1 和 plexin B2 的表达均上调，并且两种 plexin 受体的沉默抑制了 KD 血清处理的 HCAEC 中 IL-1、IL-6 和 IL-8 的过度表达。因此，我们的研究结果表明，从中性粒细胞释放的 sSema4D 通过 plexin B1 和 plexin B2 促进 ECs 炎症细胞因子的产生，从而参与 KD-CALs 的发病机制，Sema4D 可能是 KD-CALs 的新预测因子和 KD 抗炎策略的候选治疗靶点。
