靶向髓样分化蛋白2通过MAPK和NF-κB信号通路抑制炎症和铁下垂改善类风湿关节炎。

IF 4.8 3区 医学 Q1 GENETICS & HEREDITY
Lirun Zhou, Tong Yang, Shujie Zhang, Dandan Liu, Chenran Feng, Jiang Ni, Qiaoli Shi, Yanqing Liu, Yuqing Meng, Yongping Zhu, Huan Tang, Jigang Wang, Ang Ma
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引用次数: 0

摘要

髓样分化蛋白2 (MD2)是先天免疫系统中toll样受体4 (TLR4)的共受体,已成为抗炎治疗的一个有希望的靶点。类风湿性关节炎(RA)是一种以持续滑膜炎症和进行性关节破坏为特征的慢性自身免疫性疾病,由于缺乏有效的治疗选择,仍然是治疗上的挑战。在本研究中,我们探讨了MD2在RA发病和进展中的作用。我们的研究结果表明,MD2在RA患者的全血和滑膜组织中都过表达。此外,MD2在胶原诱导的RA小鼠模型中表达上调。MD2敲除可显著缓解RA的关键症状,包括改善体重、减轻足跖肿胀、减少骨破坏和软骨侵蚀。此外,MD2缺乏导致血清炎症细胞因子水平显著降低,滑膜组织内炎症蛋白表达减少。值得注意的是,动物模型显示MD2基因消融在关节炎病理生理中具有有效的抗铁下垂作用。这种保护作用通过药理学干预在细胞水平上得到了再现,其中以md2为靶点的抑制剂有效地减轻了脂多糖诱导的小鼠巨噬细胞中的铁细胞死亡,这一点得到了谷胱甘肽耗竭和脂质过氧化等特征性生物标志物的证明。机制上,MD2敲除后铁下垂和炎症的减少与滑膜组织中丝裂原活化蛋白激酶(MAPK)和核因子κ b (NF-κB)信号通路的抑制有关。这些结果表明,MD2在RA的炎症反应和铁下垂中都起着关键作用。因此,MD2代表了RA发病机制的关键介质和治疗这种使人衰弱的疾病的创新治疗靶点。关键信息:类风湿性关节炎发病后滑膜组织中MD2表达上调。MD2敲除可减轻类风湿关节炎小鼠的骨破坏、软骨侵蚀和炎症。MD2缺乏通过抑制MAPK和NF-κB信号通路诱导的铁下垂来减轻小鼠类风湿关节炎。MD2可能作为类风湿关节炎的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting myeloid differentiation protein 2 ameliorates rheumatoid arthritis by inhibiting inflammation and ferroptosis via MAPK and NF-κB signaling pathways.

Myeloid differentiation protein 2 (MD2), a co-receptor of toll-like receptor 4 (TLR4) in the innate immune system, has emerged as a promising target for anti-inflammatory therapies. Rheumatoid arthritis (RA), a chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint destruction, remains a therapeutic challenge due to the lack of effective treatment options. In this study, we investigated the role of MD2 in the pathogenesis and progression of RA. Our findings show that MD2 is overexpressed in both the whole blood and synovial tissues of RA patients. Furthermore, MD2 expression was upregulated in collagen-induced RA mouse models. MD2 knockout significantly alleviated key symptoms of RA, including improved body weight, reduced paw swelling, and decreased bone destruction and cartilage erosion. Additionally, MD2 deficiency led to a significant reduction in serum levels of inflammatory cytokines and a decrease in the expression of inflammatory protein within synovial tissue. Notably, animal models revealed that genetic ablation of MD2 exerts potent anti-ferroptosis effects in arthritic pathophysiology. This protective effect was recapitulated at the cellular level through pharmacological interventions, where MD2-targeting inhibitors effectively attenuated lipopolysaccharide-induced ferroptotic cell death in murine macrophages, as evidenced by characteristic biomarkers including glutathione depletion and lipid peroxidation. Mechanistically, the reduction in ferroptosis and inflammation following MD2 knockout was associated with the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the synovial tissue. These results suggest that MD2 plays a critical role in both the inflammatory response and ferroptosis, in the context of RA. Consequently, MD2 represents a key mediator of RA pathogenesis and an innovative therapeutic target for the treatment of this debilitating disease. KEY MESSAGES: MD2 expression is upregulated in synovial tissue following the onset of rheumatoid arthritis. MD2 knockout alleviates bone destruction, cartilage erosion, and inflammation in rheumatoid arthritis mice. MD2 deficiency mitigates rheumatoid arthritis in mice by inhibiting ferroptosis induced by the MAPK and NF-κB signaling pathways. MD2 may serve as a potential therapeutic target for rheumatoid arthritis.

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来源期刊
Journal of Molecular Medicine-Jmm
Journal of Molecular Medicine-Jmm 医学-医学:研究与实验
CiteScore
9.30
自引率
0.00%
发文量
100
审稿时长
1.3 months
期刊介绍: The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to: Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research. Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.
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