Id2 exacerbates the development of rheumatoid arthritis by increasing IFN-γ production in CD4+ T cells

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-03-06 DOI:10.1002/ctm2.70242

Haoyang Sun, Jinlin Miao, Kui Zhang, Peiyan Zhang, Haomiao Shen, Jiawei Wang, Bei Zhang, Junfeng Jia, Zhaohui Zheng, Ping Zhu

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Abstract

Purpose

This research investigates the role of inhibitor of differentiation 2 (Id2) in the synthesis of pro-inflammatory cytokines, specifically interferon-γ (IFN-γ) and interleukin-17 (IL-17), by various subsets of T cells, and its pathogenic role in rheumatoid arthritis (RA).

Methods

Flow cytometry was employed to assess T-cell activation and Id2 expression in 72 RA patients and 23 healthy controls. In vitro, peripheral blood mononuclear cells were treated with either an Id2 inhibitor or a T-cell co-stimulation inhibitor. An in vivo collagen-induced arthritis (CIA) model was established using T-cell-specific Id2 knockout mice. Additionally, follow-up observations were conducted among treated RA patients.

Results

T-cell activation levels in RA synovial fluid were significantly elevated. A positive correlation was found between increased IFN-γ and Id2 expression. In vitro, antagonising Id2 reduced IFN-γ production after T-cell activation. T-cell-specific Id2 knockout mice exhibited a diminished occurrence and severity of CIA, along with a significant decrease in IFN-γ expression. Clinical monitoring indicated that Id2-induced circulating T-cell IFN-γ expression significantly decreased following treatment with the T-cell activation inhibitor abatacept.

Conclusion

The data suggest that high Id2 expression is a critical regulator of pro-inflammatory cytokine upregulation, particularly IFN-γ, by hyperactivated T cells in RA, potentially exacerbating the disease. Inhibiting Id2 expression or function may offer new therapeutic approaches for RA joint inflammation.

Key points

Pro-inflammatory cytokines are significantly upregulated in the synovial fluid T cells in rheumatoid arthritis patients.
The expression of pro-inflammatory cytokine interferon-γ (IFN-γ) positively correlates with the high expression of inhibitor of differentiation 2 (Id2).
The inhibition or ablation of Id2 can effectively suppress IFN-γ production and the onset and progression of arthritis.

Abstract Image

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Id2通过增加CD4+ T细胞中IFN-γ的产生而加剧类风湿关节炎的发展

目的本研究探讨分化抑制因子2 （Id2）在不同T细胞亚群合成促炎细胞因子，特别是干扰素-γ (IFN-γ)和白细胞介素-17 （IL-17）中的作用及其在类风湿关节炎（RA）中的致病作用。方法采用流式细胞术检测72例RA患者和23例健康对照者的t细胞活化和Id2表达。体外，用Id2抑制剂或t细胞共刺激抑制剂处理外周血单个核细胞。用t细胞特异性Id2敲除小鼠建立了体内胶原诱导关节炎（CIA）模型。此外，对接受治疗的RA患者进行了随访观察。结果RA滑膜液t细胞活化水平明显升高。IFN-γ的升高与Id2的表达呈正相关。体外，拮抗Id2可减少t细胞活化后IFN-γ的产生。t细胞特异性Id2敲除小鼠表现出CIA发生率和严重程度降低，同时IFN-γ表达显著降低。临床监测显示，使用t细胞活化抑制剂阿巴接受治疗后，id2诱导的循环t细胞IFN-γ表达显著降低。结论高Id2表达是RA中促炎细胞因子上调的关键调节因子，特别是IFN-γ，通过过度激活的T细胞，可能加剧疾病。抑制Id2的表达或功能可能为RA关节炎症提供新的治疗途径。类风湿关节炎患者滑膜液T细胞中促炎细胞因子显著上调。促炎细胞因子干扰素-γ (IFN-γ)的表达与分化抑制剂2 （Id2）的高表达呈正相关。抑制或消融Id2可以有效抑制IFN-γ的产生和关节炎的发生和进展。

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

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.