STING Deficiency Promotes Th17-Like Tfh to Aggravate the Experimental Autoimmune Uveitis.

IF 5 2区 医学 Q1 OPHTHALMOLOGY
Zhuang Li, Xiuxing Liu, Zuoyi Li, Zhiqiang Xiao, Guanyu Chen, Yangyang Li, Jun Huang, Yunwei Hu, Haixiang Huang, Wenjie Zhu, Yuxun Shi, Minzhen Wang, Yanyan Xie, Wenru Su, Xiaoqing Chen, Dan Liang
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引用次数: 0

Abstract

Purpose: The purpose of this study was to explore the underlying mechanism that Th17-like T follicular helper cells (Tfh) orchestrated by STING signaling have a pathogenic role in experimental autoimmune uveitis (EAU).

Methods: The differences of transcriptome and gene ontology (GO) pathway of Tfh between EAU and control mice were analyzed by single-cell RNA sequence (scRNA-seq) and bulk RNA sequence. Additionally, draining lymph nodes (DLNs) were extracted to verify the expression of IL-17A and IFN-γ in Tfh from EAU and control mice by flow cytometry. Then, the scRNA-seq and flow cytometry were used to explore the different proportion of Tfh between STING deficiency (Sting-/-) mice and wild type (WT) mice. In vitro, naïve CD4+ T cells were isolated from Sting-/- mice and WT mice to induce the Tfh under the induction condition. In addition, flow cytometry was used to detect the different induction ratio and the IL-17A expression between 2 groups of naïve CD4+ T cells.

Results: Compared with control mice, marked increase of Tfh was observed in EAU, accompanied by elevated levels of Th1 and Th17 cells. Moreover, Th17-related genes, such as Rorc, Il22, Il23r, Il17a, and Il17f, and the corresponding GO pathways were upregulated in Tfh from EAU. The scRNA-seq showed that a higher proportion of Tfh was observed in the DLNs from Sting-/- mice than WT mice, which was verified by flow cytometry. When STING was knocked out, the Tfh was characterized with upregulated Th17-related phenotype in vivo, and there was a higher induction ratio of Tfh whose IL-17A expression was significantly increased in vitro. Notably, the STING expression of CD4+ T cells was downregulated in the EAU. STING-deficient EAU mice displayed more severe retinal inflammation, characterized by massive infiltration of CD4+ T cells, including Th1 and Th17 subsets. Importantly, treatment with a STING agonist alleviated inflammation of EAU.

Conclusions: Th17-like Tfh cells play a pathogenic role in the EAU. STING deficiency promotes the differentiation and phenotypic transformation of Th17-like Tfh cells, exacerbating the inflammatory response in EAU. These findings highlight the potential of targeting STING to modulate Tfh cells as a therapeutic strategy for uveitis.

STING缺乏促进th17样Tfh加重实验性自身免疫性葡萄膜炎。
目的:本研究旨在探讨STING信号介导的th17样T滤泡辅助细胞(Tfh)在实验性自身免疫性葡萄膜炎(EAU)发病中的潜在机制。方法:采用单细胞RNA序列(scRNA-seq)和大体积RNA序列分析EAU小鼠与对照组Tfh转录组和基因本体(GO)通路的差异。此外,提取引流淋巴结(dln),通过流式细胞术验证EAU和对照小鼠Tfh中IL-17A和IFN-γ的表达。然后,采用scRNA-seq和流式细胞术检测STING缺乏症(STING -/-)小鼠和野生型(WT)小鼠中Tfh的比例差异。体外分别从Sting-/-小鼠和WT小鼠中分离naïve CD4+ T细胞,在诱导条件下诱导Tfh。此外,流式细胞术检测两组naïve CD4+ T细胞诱导率及IL-17A表达的差异。结果:与对照组小鼠相比,EAU中Tfh明显升高,Th1和Th17细胞水平升高。此外,th17相关基因,如Rorc、Il22、Il23r、Il17a和Il17f,以及相应的GO通路在EAU的Tfh中上调。scRNA-seq显示,Sting-/-小鼠dln中Tfh的比例高于WT小鼠,流式细胞术证实了这一点。敲除STING后,Tfh在体内表现为th17相关表型上调,Tfh在体外诱导率较高,IL-17A表达显著升高。值得注意的是,在EAU中,CD4+ T细胞的STING表达下调。sting缺陷小鼠表现出更严重的视网膜炎症,其特征是CD4+ T细胞大量浸润,包括Th1和Th17亚群。重要的是,使用STING激动剂治疗可以减轻EAU的炎症。结论:th17样Tfh细胞在EAU中起致病作用。STING缺乏促进th17样Tfh细胞的分化和表型转化,加剧EAU的炎症反应。这些发现强调了靶向STING调节Tfh细胞作为葡萄膜炎治疗策略的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.90
自引率
4.50%
发文量
339
审稿时长
1 months
期刊介绍: Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.
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