Yang Shaopeng, Li Yuqi, Ruan Rongwei, Yu Jiangping, Zhu Bo, Lou Haibin, Zhang Xiaolan, Wang Shi
Department of Endoscopy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China.
Mol Med. 2025 Apr 29;31(1):157. doi: 10.1186/s10020-025-01230-5.
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.
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.
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.
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.
尽管肠道上皮屏障功能障碍与炎症性肠病（IBD）有关，但其潜在机制仍不清楚。肿瘤坏死因子α刺激基因6（TSG-6）是一种具有抗炎特性的分泌蛋白。我们之前的研究表明TSG-6可以减轻肠道炎症和黏膜损伤。然而，其潜在机制和靶点仍不清楚。本研究旨在探讨TSG-6如何调节肠道上皮屏障及其在实验性结肠炎中的作用机制。
使用葡聚糖硫酸钠（DSS）建立IBD小鼠模型，腹腔注射或不注射TSG-6（100μg/kg或200μg/kg）。研究TSG-6对结肠炎症和肠道屏障功能的影响。对肠道样本进行无标记定量蛋白质组分析，以探索TSG-6的作用机制和治疗靶点。通过免疫共沉淀（Co-IP）和免疫荧光共定位确定分子相互作用。
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降低了结肠组织中促炎细胞因子水平。TSG-6通过促进肠上皮细胞（IECs）增殖和减轻紧密连接（TJs）损伤来恢复肠道上皮屏障。机制上，TSG-6通过直接结合POU2类同源盒3（Pou2f3）并上调其在肠道中的表达，促进簇状细胞分化并增加白细胞介素-25（IL-25）水平。
本研究表明TSG-6通过与Pou2f3相互作用作为簇状细胞分化的正向调节因子，外源性TSG-6治疗对维持肠道屏障完整性的有效性显示出其临床应用的广阔前景。
