E3 泛素连接酶 RNF180 介导 ALKBH5/SMARCA5 轴促进溃疡性结肠炎小鼠的结肠炎症和 Th17/Treg 失衡。

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2024-07-27 DOI:10.1007/s12272-024-01507-z
Kailing Wang, Fan Liu, Budumu Muchu, Jiawen Deng, Jing Peng, Yan Xu, Fujun Li, Miao Ouyang
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引用次数: 0

摘要

SMARCA5是SWI/SNF家族中的一种蛋白质,以前曾被认为通过甲基化作用与溃疡性结肠炎(UC)的发病有关。然而,SMARCA5导致结肠炎症以及Th17和Treg细胞失衡的具体分子机制仍不清楚。本研究旨在探索这些分子机制。通过葡聚糖硫酸钠诱导建立了 UC 小鼠模型,随后测量了小鼠体重、疾病活动指数(DAI)评分、结肠长度、结肠病理变化和 FITC-葡聚糖浓度。测量了 IL-17a、IFN-γ、IL-6、TNF-α、TGF-β 和 IL-10 的水平,以及 ZO-1 和 Occludin 的蛋白表达。流式细胞术用于评估 UC 小鼠脾脏和肠系膜淋巴结中 IL-17 + CD4 +(Th17 +)细胞和 FOXP3 + CD25 + CD4 +(Treg +)细胞的存在。我们观察到,在 UC 小鼠结肠组织中,SMARCA5 和 RNF180 增高,而 ALKBH5 下调。SMARCA5或RNF180敲除或ALKBH5过表达可改善UC小鼠的结肠炎症和Th17/Treg细胞失衡,表现为体重、结肠长度、FOXP3 + CD25 + CD4 + T细胞以及ZO-1、Occludin、TGF-β、IL-10和FOXP3水平的增加。它降低了 DAI 评分、IL-17 + CD4 + T 细胞以及 IL-17a、IFN-γ、IL-6、TNF-α 和 ROR-γt 的水平。ALKBH5 通过 m6A 修饰抑制了 SMARCA5 的表达,而 RNF180 则通过泛素化降低了 ALKBH5 的表达。我们的研究结果表明,RNF180通过调节ALKBH5/SMARCA5轴加重了UC小鼠的结肠炎症和Th17/Treg细胞失衡。
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E3 ubiquitin ligase RNF180 mediates the ALKBH5/SMARCA5 axis to promote colon inflammation and Th17/Treg imbalance in ulcerative colitis mice

SMARCA5, a protein in the SWI/SNF family, has been previously implicated in the development of ulcerative colitis (UC) through methylation. However, the specific molecular mechanisms by which SMARCA5 contributes to colonic inflammation and the imbalance between Th17 and Treg cells remain unclear. This study was designed to explore these molecular mechanisms. A UC mouse model was established using dextran sulfate sodium induction, followed by measurements of mouse weight, disease activity index (DAI) score, colon length, pathological changes in the colon, and FITC-dextran concentration. The levels of IL-17a, IFN-γ, IL-6, TNF-α, TGF-β, and IL-10 were measured, along with the protein expression of ZO-1 and Occludin. Flow cytometry was used to assess the presence of IL-17 + CD4 + (Th17 +) cells and FOXP3 + CD25 + CD4 + (Treg +) cells in the spleen and mesenteric lymph nodes of UC mice. We observed that SMARCA5 and RNF180 were increased, while ALKBH5 was downregulated in UC mouse colon tissue. SMARCA5 or RNF180 knockdown or ALKBH5 overexpression ameliorated the colon inflammation and Th17/Treg cell imbalance in UC mice, shown by increased body weight, colon length, FOXP3 + CD25 + CD4 + T cells, and the levels of ZO-1, Occludin, TGF-β, IL-10, and FOXP3. It decreased DAI scores, IL-17 + CD4 + T cells, and levels of IL-17a, IFN-γ, IL-6, TNF-α, and ROR-γt. ALKBH5 inhibited SMARCA5 expression via m6A modification, while RNF180 reduced ALKBH5 expression via ubiquitination. Our findings indicate that RNF180 aggravated the colon inflammation and Th17/Treg cell imbalance in UC mice by regulating the ALKBH5/SMARCA5 axis.

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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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