抑制巨噬细胞中的 METTL3 可防止肠道炎症

IF 21.8 1区 医学 Q1 IMMUNOLOGY
Huilong Yin, Zhuan Ju, Xiang Zhang, Wenjie Zuo, Yuhang Yang, Minhua Zheng, Xiaofang Zhang, Yuning Liu, Yingran Peng, Ying Xing, Angang Yang, Rui Zhang
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引用次数: 0

摘要

炎症性肠病(IBD)发病率很高,由于对其发病机制知之甚少,目前还没有令人满意的治疗方案。在这项研究中,我们发现巨噬细胞中甲基转移酶样 3(METTL3)表达的增加与结肠炎的发生相关,而巨噬细胞中 METTL3 的消耗可保护小鼠免受右旋糖酐硫酸钠(DSS)诱导的结肠炎的影响。机理分析表明,消耗 METTL3 会增加 YTHDF3 介导的磷酸甘油酸磷酸酶(PGP)的表达,从而导致葡萄糖代谢重编程和抑制 CD4+ T 辅助细胞 1(Th1)的分化。进一步分析表明,葡萄糖代谢有助于METTL3耗竭改善结肠炎症状。此外,我们还开发了两种强效的小分子 METTL3 抑制剂,即 F039-0002 和 7460-0250,它们能显著改善 DSS 诱导的结肠炎。总之,我们的研究表明,METTL3 在结肠炎的发展过程中起着至关重要的作用,并强调了靶向 METTL3 减轻肠道炎症以治疗结肠炎的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inhibition of METTL3 in macrophages provides protection against intestinal inflammation

Inhibition of METTL3 in macrophages provides protection against intestinal inflammation

Inhibition of METTL3 in macrophages provides protection against intestinal inflammation
Inflammatory bowel disease (IBD) is prevalent, and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood. In this study, we discovered that increased expression of methyltransferase-like 3 (METTL3) in macrophages was correlated with the development of colitis and that depletion of METTL3 in macrophages protected mice against dextran sodium sulfate (DSS)-induced colitis. Mechanistic characterization indicated that METTL3 depletion increased the YTHDF3-mediated expression of phosphoglycolate phosphatase (PGP), which resulted in glucose metabolism reprogramming and the suppression of CD4+ T helper 1 (Th1) cell differentiation. Further analysis revealed that glucose metabolism contributed to the ability of METTL3 depletion to ameliorate colitis symptoms. In addition, we developed two potent small molecule METTL3 inhibitors, namely, F039-0002 and 7460-0250, that strongly ameliorated DSS-induced colitis. Overall, our study suggests that METTL3 plays crucial roles in the progression of colitis and highlights the potential of targeting METTL3 to attenuate intestinal inflammation for the treatment of colitis.
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来源期刊
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
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