C5a/C5aR1 mediates IMQ-induced psoriasiform skin inflammation by promoting IL-17A production from γδ-T cells.
C5a/C5aR1 mediates IMQ-induced psoriasiform skin inflammation by promoting IL-17A production from γδ-T cells.
复制标题
C5a/C5aR1 通过促进 γ δ-T 细胞产生 IL-17A 介导 IMQ 诱导的银屑病皮肤炎症
DOI：
10.1096/fj.202000384r
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Liang Shen-Ju
中科院分区：
文献类型：
--
作者：
Zheng Quan-You;Xu Feng;Yang Yi;Sun Dao-Dong;Zhong Yu;Wu Shun;Li Gui-Qing;Gao Wei-Wu;Wang Tao;Xu Gui-Lian;Liang Shen-Ju
银屑病是一种慢性复发性炎症性皮肤病，影响全球人口的3%。越来越多的证据表明，补体系统参与其发病机制。我们以前的研究表明，C5 a/C5 aR 1通路对疾病的发展至关重要。然而，其潜在机制在很大程度上仍然未知。为了探索潜在的机制，评估了咪喹莫特（IMQ）乳膏治疗后银屑病皮肤病变和组织学变化。通过真实的实时RT-PCR检测炎性细胞因子表达。采用免疫组织化学和流式细胞术鉴定炎性细胞浸润和白细胞介素（IL-17 A）IL-17 A表达。采用C5 aR 1拮抗剂（C5 aR 1a）和PI 3 K抑制剂（wortmannin）进行体内和体外阻断实验，探讨其作用机制。C5 a/C5 aR 1通路抑制可显著减轻银屑病样皮肤病变，减少表皮增生，下调17型相关炎症基因表达，降低产生IL-17 A的γδ-T细胞应答。从机制上讲，C5 a/C5 aR 1通过PI 3 K-Akt信号传导促进后一种表型。因此，C5 aR 1缺乏明显改善了IMQ诱导的慢性银屑病样皮炎，IL-17 A表达显著降低。最后，阻断C5 aR 1信号传导进一步减少了IL-17缺陷小鼠中的银屑病样皮肤炎症。结果表明，C5 a/C5 aR 1通过上调γδ-T细胞的IL-17 A表达介导实验性银屑病和皮肤炎症。阻断C5 a/C5 aR 1/IL-17 A轴有望成为银屑病治疗的一种有前景的策略。
Psoriasis is a chronic relapsing inflammatory skin disease, affecting up to 3% of the global population. Accumulating evidence suggests that the complement system is involved in its pathogenesis. Our previous study revealed that the C5a/C5aR1 pathway is crucial for disease development. However, the underlying mechanisms remain largely unknown. To explore potential mechanisms, psoriatic skin lesions and histological changes were assessed following imiquimod (IMQ) cream treatment. Inflammatory cytokine expression was tested by real‐time RT‐PCR. Immunohistochemistry and flow cytometry were used to identify inflammatory cell infiltration and interleukin (IL‐17A) IL‐17A expression. A C5aR1 antagonist (C5aR1a) and PI3K inhibitor (wortmannin) were used for blocking experiments (both in vivo and in vitro) to explore the mechanism. C5a/C5aR1‐pathway inhibition significantly attenuated psoriasis‐like skin lesions with decreased epidermal hyperplasia, downregulated type 17‐related inflammatory gene expression, and reduced IL‐17A‐producing γδ‐T cell responses. Mechanistically, C5a/C5aR1 promoted the latter phenotype via PI3K‐Akt signaling. Consistently, C5aR1 deficiency clearly ameliorated IMQ‐induced chronic psoriasiform dermatitis, with a significant decrease in IL‐17A expression. Finally, blocking C5aR1 signaling further decreased psoriasiform skin inflammation in IL‐17‐deficient mice. Results suggest that C5a/C5aR1 mediates experimental psoriasis and skin inflammation by upregulating IL‐17A expression from γδ‐T cells. Blocking C5a/C5aR1/IL‐17A axis is expected to be a promising strategy for psoriasis treatment.