百日咳毒素诱导树突状细胞中 Wnt/β-catenin 信号通路抑制促进实验性自身免疫性葡萄膜炎的自身免疫反应。

Pertussis toxin-induced inhibition of Wnt/β-catenin signaling in dendritic cells promotes an autoimmune response in experimental autoimmune uveitis.

机构信息

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.

Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, School of Medicine, Louisville, KY, USA.

出版信息

J Neuroinflammation. 2023 Feb 4;20(1):24. doi: 10.1186/s12974-023-02707-y.

DOI:10.1186/s12974-023-02707-y

PMID:36739434

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9898909/

Abstract

BACKGROUND

Previous reports have indicated that disrupting the Wnt/β-catenin pathway in dendritic cells (DCs) may affect the progression of autoimmune inflammation; however, the factors and timing that regulate Wnt/β-catenin signaling have not been clearly understood.

METHODS

Experimental autoimmune uveitis (EAU) mice and Vogt-Koyanagi-Harada disease (VKH) patient samples were used to detect the expression of Wnt/β-catenin pathway genes. Western blot, real-time PCR, flow cytometry, and ELISA were performed to examine the expression of components of the Wnt/β-catenin pathway and inflammatory factors. DC-specific β-catenin knockout mice and 6-bromoindirubin-3'-oxime (BIO) administered mice were used to observe the effect of disrupting the Wnt pathway on EAU pathogenesis.

RESULTS

Wnt/β-catenin signaling was inhibited in DCs during the induction phase of EAU. The inhibition was mediated by pertussis toxin (PTX), which promoted DC maturation, in turn promoting pathogenic T cell proliferation and differentiation. In vivo experiments confirmed that deleting β-catenin in DCs enhanced EAU severity, and pre-injection of PTX advanced EAU onset. Administration of a Wnt activator (BIO) limited the effects of PTX, in turn ameliorating EAU.

CONCLUSIONS

Our results demonstrate that PTX plays a key role as a virulence factor in initiating autoimmune inflammation via DCs by inhibiting Wnt/β-catenin signaling in EAU, and highlight the potential mechanism by which infection can trigger apparent autoimmunity.

摘要

背景

先前的报告表明，破坏树突状细胞（DC）中的 Wnt/β-catenin 通路可能会影响自身免疫炎症的进展；然而，调节 Wnt/β-catenin 信号的因素和时间尚不清楚。

方法

使用实验性自身免疫性葡萄膜炎（EAU）小鼠和 Vogt-Koyanagi-Harada 病（VKH）患者样本来检测 Wnt/β-catenin 通路基因的表达。通过 Western blot、实时 PCR、流式细胞术和 ELISA 检测 Wnt/β-catenin 通路和炎症因子的组成部分的表达。使用 DC 特异性β-catenin 敲除小鼠和 6-溴靛红-3'-肟（BIO）处理的小鼠观察破坏 Wnt 通路对 EAU 发病机制的影响。

结果

在 EAU 的诱导期，DC 中的 Wnt/β-catenin 信号受到抑制。这种抑制是由百日咳毒素（PTX）介导的，PTX 促进 DC 成熟，进而促进致病性 T 细胞的增殖和分化。体内实验证实，在 DC 中删除β-catenin 会加重 EAU 的严重程度，而预先注射 PTX 会提前 EAU 的发病。Wnt 激活剂（BIO）的给药限制了 PTX 的作用，从而改善了 EAU。