中华皮肤科杂志 ›› 2025, Vol. 58 ›› Issue (11): 1034-1041.doi: 10.35541/cjd.20240437

• 论著 • 上一篇    下一篇

IL-27通过抑制T细胞分泌IL-17A在银屑病中发挥保护作用的机制研究

蓝之易1，2，3    陈泽毓1，2    赵梓含1，2    张希琳1，2    顾军2，3    史玉玲1，2   

  1. 1同济大学附属皮肤病医院皮肤内科，上海  200443； 2同济大学医学院银屑病研究所，上海  200443；3同济大学附属第十人民医院皮肤科，上海  200072
  • 收稿日期:2024-08-16 修回日期:2025-09-16 发布日期:2025-11-03
  • 通讯作者: 史玉玲 E-mail:shiyuling1973@tongji.edu.cn
  • 基金资助:
    国家重点研发计划（2023YFC2508106）；国家自然科学基金（82073429、82273510、82173405）；上海市教育委员会科研创新计划项目（ 2019-01-07-00-07-E00046 ）；上海申康医院发展中心临床研究项目（SHDC2020CR1014B）

Interleukin-27 exerts a protective effect against psoriasis by inhibiting the secretion of interleukin-17A from T cells: a mechanistic study

Lan Zhiyi1,2,3, Chen Zeyu1,2, Zhao Zihan1,2, Zhang Xilin1,2, Gu Jun2,3, Shi Yuling1,2   

  1. 1Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China; 2Institute of Psoriasis, Tongji University School of Medicine, Shanghai 200443, China; 3Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
  • Received:2024-08-16 Revised:2025-09-16 Published:2025-11-03
  • Contact: Shi Yuling E-mail:shiyuling1973@tongji.edu.cn
  • Supported by:
    National Key Research and Development Program of China （2023YFC2508106）; National Natural Science Foundation of China （82073429, 82273510, 82173405）; Innovation Program of Shanghai Municipal Education Commission （2019-01-07-00-07-E00046）; Clinical Research Plan of Shanghai Hospital Development Center （SHDC2020CR1014B）

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摘要： 【摘要】 目的 探究白细胞介素27（IL-27）在银屑病中发挥保护性作用的具体机制。方法 收集正常人皮肤5份和银屑病皮损6份，通过免疫组化法检测IL-27的表达。构建Il27ra基因敲除（KO）小鼠，在5只野生型（WT）及6只KO小鼠背部涂抹咪喹莫特乳膏诱导建立银屑病模型后，采用改良版银屑病面积和严重程度指数（mPASI）评估小鼠皮损情况，取皮损处组织进行苏木精-伊红（HE）染色观察表皮厚度变化。制备4只WT小鼠和3只KO小鼠皮损和皮肤引流淋巴结单细胞悬液，通过流式细胞术分析免疫细胞（T细胞、γδT细胞、中性粒细胞）变化。另分离9只WT且正常小鼠皮肤引流淋巴结细胞，使用T细胞受体（TCR）激动剂（CD3/28激活型抗体，αCD3/28）或细胞因子（IL-23 + IL-1β）刺激IL-17A的产生，后加入IL-27；并分离6例银屑病患者的外周血单个核细胞（PBMC），使用TCR激动剂刺激IL-17A的产生，后加入IL-27；使用流式细胞术和酶联免疫吸附试验（ELISA）检测分析IL-27对T细胞表达IL-17A的影响。两组间数据比较采用t检验。结果 免疫组化染色结果显示，与正常皮肤（平均荧光强度19.45 ± 2.51）相比，银屑病皮损处IL-27的表达（9.85 ± 3.07，t = 5.60，P < 0.001）显著降低。动物实验表明，与WT小鼠（mPASI为2.80 ± 0.84）相比，KO小鼠银屑病样皮肤炎症（mPASI为4.00 ± 0.89，t = 2.28，P = 0.049）显著加重。与WT小鼠（92.26 μm ± 8.76 μm）相比，KO小鼠表皮厚度（115.50 μm ± 7.69 μm，t = 4.70，P = 0.001）显著增加。与WT小鼠相比，KO小鼠皮损中T细胞（11.22% ± 2.76%比7.08% ± 0.85%）、真皮γδT细胞（4.78% ± 0.39%比2.78% ± 0.49%）占活细胞比例显著增加（t = 2.91和2.75，均P < 0.05），但中性粒细胞占比差异无统计学意义（WT：13.57% ± 8.36%，KO：14.43% ± 9.13%；t = 0.13，P = 0.902），皮肤引流淋巴结中Th17、IL-17+γδT、Th22和IL-22+γδT细胞比例也显著增加（均P < 0.05）。不同刺激物实验显示，IL-27能够显著抑制TCR激动剂诱导的小鼠γδT细胞IL-17A的表达（IL-17A相对表达量：αCD3/28组1.00 ± 0.11，αCD3/28 + IL-27组0.76 ± 0.13；t = 3.54，P = 0.004），而在有无IL-27共培养组中IL-23 + IL-1β诱导的IL-17A表达差异无统计学意义（t = 1.34，P > 0.05）。ELISA检测显示，IL-27能显著降低TCR激动剂诱导的引流淋巴结细胞培养上清液中的IL-17A浓度（αCD3/28组1 535.00 pg/ml ± 97.76 pg/ml，αCD3/28 + IL-27组1 030.00 pg/ml ± 287.90 pg/ml，t = 3.29，P = 0.031），而不能减少IL-23 + IL-1β诱导的IL-17A浓度（t = 0.09，P > 0.05）。流式细胞术分析显示，IL-27能显著抑制TCR激动剂诱导的银屑病患者T细胞中IL-17A的表达（αCD3/28组4.28 ± 3.25，αCD3/28 + IL-27组3.04 ± 2.65，t = 4.46，P = 0.007）。结论 IL-27在银屑病中可能通过抑制T细胞分泌IL-17A从而发挥保护作用。

关键词: 银屑病, 白细胞介素27, 白细胞介素17, Th17细胞, 受体, 抗原, T细胞, γ-δ

Abstract: 【Abstract】 Objective To investigate the specific mechanisms underlying the protective effect of interleukin （IL）-27 in the pathogenesis of psoriasis. Methods Five skin tissue samples from healthy individuals and 6 lesional skin samples from psoriasis patients were collected, and IL-27 expression was determined by immunohistochemical staining. Il27ra gene knockout （KO） mice were constructed. Psoriasis-like mouse models were established with topical imiquimod in 5 wild-type （WT） mice and 6 KO mice. Mouse skin lesions were evaluated using the modified Psoriasis Area and Severity Index （mPASI）, and lesional skin tissues were collected for hematoxylin and eosin （HE） staining to observe changes in epidermal thickness. Single-cell suspensions were prepared with skin lesions and skin-draining lymph nodes of 4 WT mice and 3 KO mice, and changes in immune cells （including T cells, γδ T cells, and neutrophils） were analyzed using flow cytometry. Additionally, skin-draining lymph node cells were isolated from 9 normal WT mice, and IL-17A expression was stimulated using a T-cell receptor agonist （CD3/28 activating antibodies, αCD3/28） or cytokines （IL-23 + IL-1β）, followed by the addition of IL-27; peripheral blood mononuclear cells （PBMCs） were isolated from 6 psoriasis patients, and IL-17A expression was stimulated using the T-cell receptor agonist, followed by the addition of IL-27; the effect of IL-27 on IL-17A expression in T cells was analyzed using flow cytometry and enzyme-linked immunosorbent assay （ELISA）. Measurement data were compared between two groups using the t test. Results Immunohistochemical staining revealed a significant reduction in IL-27 expression in psoriatic lesions （mean fluorescence intensity: 9.85 ± 3.07） compared with the normal skin （19.45 ± 2.51, t = 5.60, P < 0.001）. Animal experiments demonstrated that the KO mice exhibited significantly aggravated psoriasis-like skin inflammation （mPASI: 4.00 ± 0.89） and significantly increased epidermal thickness （115.50 ± 7.69 μm） compared with the WT mice （mPASI: 2.80 ± 0.84, t = 2.28, P = 0.049; epidermal thickness: 92.26 ± 8.76 μm, t = 4.70, P = 0.001）; compared with the WT mice, the KO mice showed significantly increased proportions of T cells （11.22% ± 2.76% vs. 7.08% ± 0.85%） and dermal γδ T cells （4.78% ± 0.39% vs. 2.78% ± 0.49%） among live cells in the lesions （t = 2.91, 2.75, respectively, both P < 0.05）, as well as significantly increased proportions of Th17, IL-17+ γδ T, Th22, and IL-22+ γδ T cells in the skin-draining lymph nodes （all P < 0.05）, but no significant difference in the proportion of neutrophils in the lesions （WT: 13.57% ± 8.36%, KO: 14.43% ± 9.13%; t = 0.13, P = 0.902）. Experiments with different stimuli showed that IL-27 significantly suppressed T-cell receptor agonist-induced IL-17A expression in murine γδ T cells （αCD3/28 group: 1.00 ± 0.11, αCD3/28 + IL-27 group: 0.76 ± 0.13; t = 3.54, P = 0.004）, while there was no significant difference in IL-17A expression between cells induced by IL-23 + IL-1β with the IL-27 co-culture and those without （t = 1.34, P > 0.05）. ELISA showed that IL-27 significantly reduced the IL-17A concentration in the culture supernatant of draining lymph node cells stimulated by the T-cell receptor agonist （αCD3/28 group: 1 535.00 ± 97.76 pg/ml, αCD3/28 + IL-27 group: 1 030.00 ± 287.90 pg/ml, t = 3.29, P = 0.031）, but did not reduce the IL-17A concentration induced by IL-23 + IL-1β （t = 0.09, P > 0.05）. Flow cytometry indicated that IL-27 significantly inhibited the T-cell receptor agonist-induced IL-17A expression in T cells from psoriasis patients （αCD3/28 group: 4.28 ± 3.25, αCD3/28 + IL-27 group: 3.04 ± 2.65, t = 4.46, P = 0.007）. Conclusion IL-27 appeared to play a protective role in psoriasis by suppressing IL-17A secretion from T cells.

Key words: Psoriasis, Interleukin-27, Interleukin-17, Th17 cells, Receptors, antigen, T-cell, gamma-delta

引用本文

蓝之易 陈泽毓 赵梓含 张希琳 顾军 史玉玲. IL-27通过抑制T细胞分泌IL-17A在银屑病中发挥保护作用的机制研究[J]. 中华皮肤科杂志, 2025,58(11):1034-1041. doi:10.35541/cjd.20240437

Lan Zhiyi, Chen Zeyu, Zhao Zihan, Zhang Xilin, Gu Jun, Shi Yuling, . Interleukin-27 exerts a protective effect against psoriasis by inhibiting the secretion of interleukin-17A from T cells: a mechanistic study[J]. Chinese Journal of Dermatology, 2025, 58(11): 1034-1041.doi:10.35541/cjd.20240437