Semaphorin 4D Induces an Imbalance of Th17/Treg Cells by Activating the Aryl Hydrocarbon Receptor in Ankylosing Spondylitis.
Semaphorin 4D Induces an Imbalance of Th17/Treg Cells by Activating the Aryl Hydrocarbon Receptor in Ankylosing Spondylitis.
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DOI：
10.3389/fimmu.2020.02151
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发表时间：
2020
影响因子：
7.3
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Xie J;Wang Z;Wang W
Semaphorin 4D（Sema 4D）在T细胞和破骨细胞上组成性表达，并调节T细胞增殖和骨重建。此外，一些研究表明Sema 4D参与了自身免疫的发病机制。本研究旨在探讨Sema 4D影响强直性脊柱炎（AS）发病进程的机制。血清可溶性Sema 4D（sSema 4D）水平通过酶联免疫吸附测定进行分析。在来自AS患者和健康个体的CD 4+和CD 19+细胞中评估Sema 4D的细胞表面水平和转录物。通过定量聚合酶链反应（qPCR）评估mRNA表达水平。通过流式细胞术分析从CD 4 + T细胞分化的Treg细胞和产生IL-17的T细胞（Th 17细胞）的比例。通过荧光素酶和EROD测定分析下游信号通路和靶基因的激活来检测Sema 4D的芳烃受体（AhR）激动作用。两组AS患者血清sSema 4D水平均升高，且临床特征标志物与血清sSema 4D水平相关。Sema 4D通过增强RORγt表达、降低Foxp 3表达，促进CD 4 + T细胞增殖和Th 17细胞分化，抑制Treg细胞分化，同时增加IL-17和IL-22的表达和分泌。它通过与CD 72相互作用诱导AhR靶基因CYP 1A 1的表达和活性以及XRE报告基因活性。这些发现表明，Sema 4D作为免疫应答中T细胞的有效激活剂，通过以AhR依赖的方式诱导Th 17和Treg细胞群的失衡而促进AS的炎症，表明它是AS发病机制的重要参与者。
Semaphorin 4D (Sema4D) is constitutively expressed on T cells and osteoclasts, and regulates T cell proliferation and bone remodeling. In addition, several studies have shown that Sema4D is involved in the pathogenesis of autoimmunity. We undertook this study to investigate the mechanism by which Sema4D affects the pathogenic progress of ankylosing spondylitis (AS). Soluble Sema4D (sSema4D) levels in serum were analyzed by enzyme-linked immunosorbent assay. The cell surface levels and transcripts of Sema4D were evaluated in CD4 + and CD19 + cells from the AS patients and healthy individuals. The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from CD4 + T cells were analyzed by flow cytometric analysis. The aryl hydrocarbon receptor (AhR) agonistic effect of Sema4D was detected by analyzing the activation of downstream signaling pathways and target genes using Luciferase and EROD assay. Levels of sSema4D were elevated in both serum from AS patients, and clinical features markers were correlated with serum sSema4D levels. Sema4D facilitated CD4 + T cells proliferation and Th17 cells differentiation and inhibited Treg cells differentiation by enhancing RORγt expression and reducing Foxp3 expression, with increasing expression and secretion of IL-17 and IL-22. It induced the expression and activity of AhR target gene CYP1A1 and XRE reporter activity via interaction with CD72. These findings indicate that Sema4D as a potent activator of T cells in the immune response contributes to the inflammation of AS by inducing imbalance in Th17 and Treg cell populations in an AhR-dependent manner, suggesting it is a crucial participant in AS pathogenesis.