IFIT3 mediates TBK1 phosphorylation to promote activation of pDCs and exacerbate systemic sclerosis in mice

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2024-09-20 DOI:10.1002/ctm2.1800

Xiangyang Huang, Yi Liu, Xia Rong, Yiheng Zhao, Dan Feng, Jun Wang, Wanhong Xing

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引用次数: 0

Abstract

Objective

To assess the impact of the IFIT3/TBK1 signalling pathway in activating plasmacytoid dendritic cells (pDCs) and its role in the development of SSc.

Methods

Utilized single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptome RNA sequencing to reveal the differential abundance of pDCs and the role of the key gene IFIT3 in SSc. Conducted in vitro cell experiments to evaluate the effect of IFIT3/TBK1 signalling pathway intervention on pDC activation cytokine release and fibroblast function. Constructed an IFIT3^−/− mouse model using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing to assess the potential benefits of intervening in the IFIT3/TBK1 signalling pathway on skin and lung fibrosis in the SSc mouse model.

Results

The IFIT3/TBK1 signalling pathway plays a crucial role in activating pDCs, with IFIT3 acting as an upstream regulator of TBK1. Intervention in the IFIT3/TBK1 signalling pathway can inhibit pDC activation cytokine release and impact fibroblast function. The IFIT3^−/− mouse model shows potential benefits of targeting the IFIT3/TBK1 signalling pathway in reducing skin and lung fibrosis in the SSc mouse model.

Conclusion

This study provides new insights into potential therapeutic targets for SSc, highlighting the critical role of the IFIT3/TBK1 signalling pathway in SSc development.

Highlights

This study elucidates the pivotal role of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc).
This study identified the key regulatory gene involved in systemic sclerosis (SSc) as IFIT3.
This study has found that IFIT3 functions as an upstream regulatory factor, activating TBK1.
This study provides Evidence of the regulatory effects of the IFIT3/TBK1 pathway on plasmacytoid dendritic cells (pDCs).
This study validated the therapeutic potential using the IFIT3^−/− mouse model.

Abstract Image

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IFIT3 介导 TBK1 磷酸化，促进 pDC 的活化并加剧小鼠的系统性硬化症

目的评估 IFIT3/TBK1 信号通路在激活浆细胞树突状细胞（pDCs）中的影响及其在 SSc 发病中的作用。方法利用单细胞 RNA 测序（scRNA-seq）和高通量转录组 RNA 测序来揭示 pDCs 的不同丰度以及关键基因 IFIT3 在 SSc 中的作用。进行体外细胞实验，评估 IFIT3/TBK1 信号通路干预对 pDC 活化细胞因子释放和成纤维细胞功能的影响。利用簇状规则间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9（Cas9）基因编辑技术构建IFIT3-/-小鼠模型，以评估干预IFIT3/TBK1信号通路对SSc小鼠模型中皮肤和肺纤维化的潜在益处。结果 IFIT3/TBK1信号通路在激活pDC中起着至关重要的作用，其中IFIT3是TBK1的上游调节因子。干预 IFIT3/TBK1 信号通路可抑制 pDC 激活细胞因子的释放并影响成纤维细胞的功能。IFIT3-/- 小鼠模型表明，靶向 IFIT3/TBK1 信号通路可减少 SSc 小鼠模型中的皮肤和肺纤维化。结论本研究为SSc的潜在治疗靶点提供了新的见解，强调了IFIT3/TBK1信号通路在SSc发展过程中的关键作用。亮点本研究阐明了浆细胞树突状细胞（pDCs）在系统性硬化症（SSc）中的关键作用。这项研究确定了参与系统性硬化症（SSc）的关键调控基因为 IFIT3。该研究发现，IFIT3 作为上游调控因子激活了 TBK1。这项研究为 IFIT3/TBK1 通路对质类树突状细胞（pDCs）的调控作用提供了证据。这项研究利用 IFIT3-/- 小鼠模型验证了治疗潜力。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.