Blockade of IL-7Rα alleviates collagen-induced arthritis via inhibiting Th1 cell differentiation and CD4+ T cell migration
Blockade of IL-7Rα alleviates collagen-induced arthritis via inhibiting Th1 cell differentiation and CD4+ T cell migration
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DOI：
10.1016/j.molimm.2016.09.017
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发表时间：
2016-11-01
影响因子：
3.6
通讯作者：
Nie, Hong
中科院分区：
文献类型：
--
作者：
Cai, Li;Xu, Haiyan;Nie, Hong
T细胞反应在类风湿关节炎(RA)的发病和发展中起着至关重要的作用。IL-7/IL-7R轴对CD4(+)T细胞的增殖、分化、存活和迁移有重要影响。然而，阻断IL-7/IL-7R轴信号通路是否能缓解RA以及可能的治疗机制仍不清楚。本文建立了胶原性关节炎(CIA)模型，并观察了IL-7Rα抗体对CIA小鼠的治疗作用。结果表明，IL-7Rα抗体可显著减轻CIA小鼠的临床症状，并伴有脾和关节中CD4(+)T细胞数量的减少。在IL-7Rα抗体处理的小鼠中，观察到CII特异性的CD4(+)T细胞的增殖和炎性细胞因子的mRNA表达减少。随后，IL-7ra抗体体内处理可下调Th1、Th17细胞百分率及T-bet和ROR-Gamma-t基因的mRNA表达。此外，IL-7在体外可促进Th1细胞分化，而对Th17细胞分化无影响。此外，IL-7Rα抗体可降低关节CIA(+)T细胞表面趋化因子受体CCR7、CXCR3、CXCR6和XCR1及趋化因子CXCL2的mRNA表达。提示IL-7Rα抗体通过抑制CII特异性的CD4(+)T细胞增殖，减少Th1细胞分化，抑制CD4(+)T细胞向关节病变部位迁移，从而治疗CIA小鼠。本研究表明IL-7Rα是RA潜在的治疗靶点。(C)2016爱思唯尔有限公司。保留所有权利。
T cell response is crucial to the pathogenesis and progression of rheumatoid arthritis (RA). IL-7/IL-7R axis has significant effect on CD4(+) T cell response, including proliferation, differentiation, survival and migration. However, whether blockade of IL-7/IL-7R axis signaling can relieve RA and what is the potential treatment mechanisms are still remaining unclear. In this paper, we established collagen-induced arthritis (CIA) model and observed the effect of IL-7R alpha antibody in the treatment of CIA mice. It is demonstrated that IL-7R alpha antibody significantly alleviated clinical symptoms of CIA mice, accompanied with reduced CD4(+) T cell number in both spleen and joints. Decreased CII-specific CD4(+) T cell proliferation and reduced mRNA expression of inflammatory cytokines in IL-7R alpha antibody-treated mice were observed. Subsequently, IL-7Ra antibody treatment in vivo downregulated the percentages of Th1 and Th17 cells and the mRNA expression of T-bet and ROR gamma t gene. Moreover, it was found that IL-7 promoted Th1 cell differentiation in vitro, while having no effect on Th17 cell differentiation. In addition, administration of IL-7R alpha antibody reduced the mRNA expression of chemokine receptors (CCR7, CXCR3, CXCR6 and XCR1) on CIA(+) T cells and chemokine CXCL2 in joints. The results suggested that IL-7R alpha antibody treated CIA mice via the inhibition of CII-specific CD4(+) T cell proliferation, the reduction of Th1 cell differentiation and the restrain of CD4(+) T cell migration to joint lesion site. This investigation indicates that IL-7R alpha is a potential therapeutic target for RA. (C) 2016 Elsevier Ltd. All rights reserved.