MOR106通过阻断JAK2/STAT3信号通路抑制IL-17C介导的Tfh细胞分化来减轻特应性皮炎小鼠炎症

MOR106 alleviates inflammation in mice with atopic dermatitis by blocking the JAK2/STAT3 signaling pathway and inhibiting IL-17C-mediated Tfh cell differentiation

目的 探讨特应性皮炎(AD)模型中白细胞介素17C(IL-17C)介导滤泡辅助性T(Tfh)细胞分化的意义。方法BALB/c小鼠分为对照组、AD模型组、低剂量MOR106处理组、高剂量MOR106处理组,每组8只。除对照组外,其余各组均用2,4-二硝基氯苯(DNCB)处理建立AD模型,低剂量和高剂量MOR106处理组分别给与5 mg/kg或10 mg/kg MOR106(抗IL-17C huIgG1)处理。通过流式细胞术分析小鼠外周血中Tfh细胞亚群的分化,并采用Western blot法检测皮肤组织中Janus激酶2/信号转导子与转录激活子3(JAK2/STAT3)信号通路蛋白表达。结果 与对照组相比,AD模型组皮炎严重程度评分、两耳之间的质量差异、脾脏质量、脾脏指数均显著增加,AD组小鼠的Tfh细胞亚群显示去调节分化,导致外周血中CD4^(+)CXC趋化因子受体5(CXCR5)^(+)γ干扰素(IFN-γ)^(+)Tfh1细胞、 CD4^(+)CXCR5^(+)IL-17A^(+)Tfh17细胞和CD4^(+)CXCR5^(+)IL-21^(+)Tfh21细胞的百分比显著增加,以及CD4^(+)CXCR5^(+)IL-10^(+)Tfh10细胞和CD4^(+)CXCR5^(+)叉头盒转录因子3(FOXP3)^(+)滤泡调节性T(Tfr)细胞的百分比显著减少,磷酸化的JAK2(p-JAK2)、 p-STAT3蛋白水平显著增加;与AD模型组相比,MOR106处理组皮炎严重程度评分、两耳之间的质量差异、脾脏质量、脾脏指数均显著降低。MOR106处理有效地逆转AD小鼠外周血中Tfh1细胞、 Tfh10细胞、 Tfh17细胞、 Tfh21细胞和Tfr细胞的这些变化趋势。与AD组相比,低剂量和高剂量MOR106处理组小鼠p-JAK2、 p-STAT3蛋白水平显著降低。结论 MOR106通过阻断JAK2/STAT3信号通路、抑制IL-17C介导的Tfh细胞分化来减轻AD小鼠炎症反应。

Objective To explore the significance of interleukin-17C(IL-17C)-mediated follicular helper T cell(Tfh)differentiation in atopic dermatitis(AD)model.Methods BALB/c mice were divided into control group,AD model group,low-dose MOR106(anti-IL-17C huIgG1)(MDR106-L)treatment group and high-dose MOR106(MOR106-H)treatment group,8 mice in each group.Except for the control group,all the other groups were treated with 2,4-dinitrochlorobenzene(DNCB)to establish AD models.The low-dose and high-dose MOR106 groups were treated with 5 mg/kg or 10 mg/kg MOR106 respectively.The differentiation of Tfh cell subsets in peripheral blood of mice was analyzed by flow cytometry,and the expression of Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signal pathway protein in skin tissue was detected by Western blot analysis.Results Compared with the control group,the dermatitis severity score,mass difference between two ears,spleen mass and spleen index of DNCB group increased significantly,while those of MOR106-L group and MOR106-H group decreased significantly.Compared with the control group,the Tfh subgroup of AD mice showed deregulated differentiation,resulting in a significant increase in the percentage of CD4^(+)CXCR5^(+)IFN-γ^(+)Tfh1 cells,CD4^(+)CXCR5^(+)IL-17A^(+)Tfh17 and CD4^(+)CXCR5^(+)IL-21^(+)Tfh21 cells,and a significant decrease in the percentage of CD4^(+)CXCR5^(+)IL-10^(+)Tfh10 cells and CD4^(+)CXCR5^(+)FOXP3^(+)Tfr cells in peripheral blood.The protein levels of phosphorylated JAK2(p-JAK2)and p-STAT3 were significantly increased.MOR106 effectively reversed these changes of Tfh1,Tfh10,Tfh17,Tfh21 and Tfr cells in peripheral blood of AD mice.Compared with AD group,the levels of p-JAK2 and p-STAT3 protein in low-dose and high-dose MOR106 treatment groups decreased significantly.Conclusion MOR106 can reduce the inflammatory response of AD mice by blocking JAK2/STAT3 signaling pathway and inhibiting the differentiation of Tfh cells mediated by IL-17C.