Exogenous TSG-6 treatment alleviates DSS-induced colitis in mice by modulating Pou2f3 and promoting tuft cells differentiation.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-04-29 DOI:10.1186/s10020-025-01230-5

Shaopeng Yang, Yuqi Li, Rongwei Ruan, Jiangping Yu, Bo Zhu, Haibin Lou, Xiaolan Zhang, Shi Wang

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引用次数: 0

Abstract

Background: Whereas intestinal epithelial barrier dysfunction is implicated in inflammatory bowel disease (IBD), the underlying mechanisms remain elusive. Tumor necrosis factor α stimulated gene 6 (TSG-6) is a secretory protein with anti-inflammatory properties. Our previous research demonstrated TSG-6 can relieve intestinal inflammation and mucosal damage. However, the underlying mechanism and targets remain unclear. This research sought to explore how TSG-6 regulates the intestinal epithelial barrier and its mechanistic role in experimental colitis.

Methods: IBD mouse model was generated using dextran sodium sulfate (DSS), with or without intraperitoneal injection of TSG-6(100 µg/kg or 200 µg/kg). The effects of TSG-6 on colonic inflammation and intestinal barrier function were investigated. Label-free quantitative proteomic analysis was performed on intestinal samples to explore the mechanism and therapeutic target of TSG-6. Molecular interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence colocalization.

Results: TSG-6 treatment significantly attenuated DSS-induced colitis symptoms and inflammatory cell infiltration. Microarray analysis revealed that TSG-6 decreased pro-inflammatory cytokine levels in colon tissue. TSG-6 restored the intestinal epithelial barrier through the promotion of intestinal epithelial cells (IECs) proliferation and mitigation of tight junctions (TJs) damage. Mechanistically, TSG-6 promoted tuft cells differentiation and increased interleukin-25 (IL-25) levels by directly binding to Pou class 2 homeobox 3(Pou2f3) and up-regulating its expression in the gut.

Conclusions: This study demonstrated TSG-6 as a positive regulator of tuft cells differentiation by interacting with Pou2f3, and the effectiveness of exogenous TSG-6 treatment on maintaining intestinal barrier integrity showed a promising potential for its clinical application.

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外源性TSG-6通过调节Pou2f3和促进簇状细胞分化，减轻dss诱导的小鼠结肠炎。

背景：虽然肠上皮屏障功能障碍与炎症性肠病（IBD）有关，但其潜在机制尚不明确。肿瘤坏死因子α刺激基因6 （TSG-6）是一种具有抗炎作用的分泌性蛋白。我们前期的研究表明，TSG-6可以缓解肠道炎症和黏膜损伤。然而，潜在的机制和目标仍不清楚。本研究旨在探讨TSG-6如何调节肠上皮屏障及其在实验性结肠炎中的机制作用。方法：采用右旋糖酐硫酸钠（DSS）制备IBD小鼠模型，腹腔注射或不注射TSG-6（100µg/kg或200µg/kg）。观察TSG-6对大鼠结肠炎症及肠道屏障功能的影响。对肠道样品进行无标记定量蛋白质组学分析，探讨TSG-6的作用机制和治疗靶点。通过共免疫沉淀（Co-IP）和免疫荧光共定位测定分子相互作用。结果：TSG-6治疗显著减轻了dss诱导的结肠炎症状和炎症细胞浸润。微阵列分析显示，TSG-6可降低结肠组织中促炎细胞因子的水平。TSG-6通过促进肠上皮细胞（IECs）增殖和减轻紧密连接（TJs）损伤来恢复肠上皮屏障。机制上，TSG-6通过直接结合Pou class 2 homobox 3（Pou2f3）并上调其在肠道中的表达，促进簇状细胞分化，增加白细胞介素-25 （IL-25）水平。结论：本研究证实TSG-6通过与Pou2f3相互作用，对簇状细胞分化具有正向调节作用，外源性TSG-6处理对维持肠道屏障完整性的有效性具有良好的临床应用前景。

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

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.