C5a/C5aR1通过促γδ T细胞IL-17A表达介导IMQ诱导的小鼠银屑病样皮炎

doi:10.16352/j.issn.1001-6325.2022.09.1325

基础医学与临床 ›› 2022, Vol. 42 ›› Issue (9): 1325-1332.doi: 10.16352/j.issn.1001-6325.2022.09.1325

• 研究论文 • 下一篇

C5a/C5aR1通过促γδ T细胞IL-17A表达介导IMQ诱导的小鼠银屑病样皮炎

郑权友¹, 梁申菊², 舒勇¹, 周山¹, 钟渝¹, 盛芬¹, 唐铭君^1*

1. 中国人民解放军陆军军医大学陆军军医大学第一附属医院中国人民解放军陆军第九五八医院肾病泌尿科, 重庆 400020;
2. 中国人民解放军陆军特色医学中心风湿免疫科,重庆 400042

收稿日期:2021-07-07 修回日期:2021-12-13 出版日期:2022-09-05 发布日期:2022-09-02
通讯作者: tangmingjun1987@163.com
基金资助:
国家自然科学基金 (81900628);重庆市自然科学基金(cstc2018jcyjAX0260)

C5a/C5aR1 mediates the IMQ-induced psoriatic skin inflammation via promoting IL-17A expression by γδ T cells in mice

ZHENG Quan-you¹, LIANG Shen-ju²,SHU Yong¹, ZHOU Shan¹, ZHONG¹ Yu, SHENG Fen¹, TANG Ming-jun^1*

1. Department of Nephrology and Urology, the 958th Hospital of PLA Army, the First Affiliated Hospital, Army Medical University, Chongqing 400020;
2. Department of Rheumatism and Immunology, Army Medical Center of PLA, Chongqing 400042,China

Received:2021-07-07 Revised:2021-12-13 Online:2022-09-05 Published:2022-09-02

摘要/Abstract

摘要： 目的探讨补体C5a/C5aR1通过促γδ T细胞IL-17A表达介导咪喹模特(IMQ)诱导小鼠银屑病样皮炎的作用及机制。方法建立IMQ诱导银屑病样皮炎模型小鼠,比较C5aR1^+/+ 及 C5aR1^-/-小鼠银屑病样皮炎程度。免疫组化(IHC)检测皮损组织局部T细胞(CD3)及中性粒细胞(Ly-6G)浸润,炎性因子IL-17A和TNF-α的表达。流式细胞测量术(FCM)检测腋窝引流淋巴结及皮损局部IL-17A表达及其主要来源细胞亚群。C5aR1a阻断C5a/C5aR1通路后,检测IMQ诱导银屑病皮炎程度、IL-17A表达情况。此外,分离小鼠脾脏淋巴细胞,经C5a、IL-23及C5aR1a等体外刺激后,检测γδ-T细胞IL-17A表达。结果在IMQ诱导银屑病样皮炎模型小鼠中,C5aR1^-/- 小鼠皮损表型较C5aR1^+/+小鼠明显减轻,并伴有T细胞及中性粒细胞浸润减少,炎性因子IL-17A和TNF-α表达明显下调(P＜0.05)。FCM检测发现C5aR1^-/-小鼠腋窝引流淋巴结及皮损组织局部IL-17A⁺细胞频率显著减低,IL-17A主要由 γδ CD3⁺ TCR⁺T细胞分泌。C5aR1a阻断C5a/C5aR1通路后IMQ诱导银屑病皮炎程度及IL-17A表达明显下调(P＜0.05)。此外,C5aR1a显著下调C5a+IL-23诱导的γδ T细胞IL-17A表达。结论补体C5a/C5aR1通路促γδ T细胞IL-17A表达介导咪喹模特诱导小鼠银屑病样皮炎。特异性阻断该通路有望成为银屑病治疗的新靶点。

关键词: 银屑病, C5a/C5aR1通路, 白细胞介素-17A(IL-17A), γδ T细胞

Abstract: Objective To explore the effects and underlying mechanism of C5a/C5aR1 pathway in mediating imiquimod (IMQ)-induced psoriatic skin inflammation by increasing IL-17A expression in γδ T cells. Methods C5aR1^+/+ and C5aR1^-/- mice were treated with IMQ or control Vasline cream for 6 consecutive days. The psoriatic skin inflammation was monitored. Inflammatory cells infiltration (T cells and neutrophils) and cytokines expression (IL-17A and TNF-α) were tested by immunohistochemistry (IHC). The percentages and cellular sources of IL-17A in both draining lymph nodes and skin lesions were analyzed by flow cytometry (FCM). Before IMQ application,C5aR1a peptide was injected into C5aR1^+/+ mice and the psoriatic skin lesions as well as IL-17A expression were examined. Additionally, the isolated spleen lymphocytes were stimulated with C5a, IL23 or C5aR1a and then tested with FCM for the expression of IL-17A in γδ T cells. Results It was shown that C5aR1 deficiency clearly ameliorated IMQ induced psoriatic skin inflammation and was coupled with decreased keratinocytes proliferation, attenuated CD3 positive T cells and neutrophils, alleviated cytokines expression (IL-17A and TNF-α). FCM results indicated that C5aR1 loss significantly decreased the percentages of IL-17A positive cells in both draining lymph nodes and skin lesions, and γδ CD3⁺ TCR⁺ T cell was proved to be the major source of IL-17A. In consistent with that, blocking C5a/C5aR1 pathway with C5aR1a peptide remarkably alleviated IMQ induced skin lesions and IL-17A responses. Moreover, blocking C5a/C5aR1 with C5aR1a significantly down-regulated IL-17A expression in γδ T cells in vitro. Conclusions This study indicates that C5a/C5aR1 signaling plays an essential role in the pathogenesis of psoriatic lesions by enhancing IL-17A expression by γδ T cells. Blocking C5a/C5aR1 pathway is a promise strategy in the treatment of psoriasis patients.

Key words: psoriasis, C5a/C5aR1 pathway, interleukin-17A(IL-17A), γδ T cells

中图分类号:

R758.29

郑权友, 梁申菊, 舒勇, 周山, 钟渝, 盛芬, 唐铭君. C5a/C5aR1通过促γδ T细胞IL-17A表达介导IMQ诱导的小鼠银屑病样皮炎[J]. 基础医学与临床, 2022, 42(9): 1325-1332.

ZHENG Quan-you, LIANG Shen-ju,SHU Yong, ZHOU Shan, ZHONG Yu, SHENG Fen, TANG Ming-jun. C5a/C5aR1 mediates the IMQ-induced psoriatic skin inflammation via promoting IL-17A expression by γδ T cells in mice[J]. Basic & Clinical Medicine, 2022, 42(9): 1325-1332.

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C5a/C5aR1通过促γδ T细胞IL-17A表达介导IMQ诱导的小鼠银屑病样皮炎

C5a/C5aR1 mediates the IMQ-induced psoriatic skin inflammation via promoting IL-17A expression by γδ T cells in mice

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