Toll-like receptor 4 (TLR4) deficiency aggravates dextran sulfate sodium (DSS)-induced intestinal injury by down-regulating IL6, CCL2 and CSF3
Toll-like receptor 4 (TLR4) deficiency aggravates dextran sulfate sodium (DSS)-induced intestinal injury by down-regulating IL6, CCL2 and CSF3
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Toll 样受体 4 (TLR4) 缺陷通过下调 IL6、CCL2 和 CSF3 加重葡聚糖硫酸钠 (DSS) 诱导的肠道损伤
DOI：
10.21037/atm.2019.12.28
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发表时间：
2019-12-01
影响因子：
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通讯作者：
Wang, Hao
中科院分区：
文献类型：
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作者：
Shi, Yun-Jie;Hu, Shi-Jie;Wang, Hao
背景：溃疡性结肠炎（UC）是一种炎症性肠病（IBD），会导致人体消化道出现长期炎症和溃疡。 TLR4对肠上皮的修复作用尚不清楚。方法：通过与野生型（WT）小鼠比较，以Toll样受体4（TLR4）敲除小鼠（TLR4-KO）作为葡聚糖硫酸钠（DSS）诱导的结肠炎模型，探讨TLR4信号在肠道损伤中的作用。采用高通量 RNA-Seq、RT-qPCR 和 ELISA 来筛选和验证 WT 和 TLR4-KO 小鼠肠道基因的关键差异。在肠道细胞系中进行了核心失调因子的功能研究。结果：我们发现LPS（TLR4激动剂）和TLR4-KO加重了DSS诱导的肠道损伤。与WT小鼠相比，TLR4-KO小鼠肠道中IL6、CCL2、CSF3、IL11、Ccnb1、Ccnd1和TNF-α显着降低，Fas和FasL增加。在用 LPS 处理的 CT-26 细胞中，IL6、CCL2、CSF3、Fas 和 FasL 均有所增加。结合上述数据和KEGG富集，可以推测TLR4-KO可能通过减弱细胞周期、细胞因子-细胞因子受体相互作用、Toll样受体信号通路，增强细胞凋亡通路，加重DSS诱导的肠道损伤。在核心失调因子的功能研究中，发现LPS、IL6、IL11、CSF3、CCL2、S100A8、S100A9和Mmp3经DSS处理后可提高结肠癌细胞系的活力并降低小鼠结肠癌细胞的凋亡率。然而，Jo-2（Fas激动性单克隆抗体）在DSS处理的结肠癌细胞中发挥相反的作用。结论：TLR4对DSS诱导的肠道损伤具有修复作用，并上调IL6、CCL2和CSF3。 Fas 和 FasL 增强了 DSS 诱导的小鼠结肠损伤，但可能与 TLR4 信号传导关系不大。
Background: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair role of TLR4 in the intestinal epithelium is still unknown.Methods: By comparing to wild-type (WT) mice, Toll-like receptor 4 (TLR4)-knockout mice (TLR4-KO) were used as dextran sulfate sodium (DSS)-induced colitis models to explore the role of TLR4 signaling in intestinal injury. High-throughput RNA-Seq, RT-qPCR and ELISA were performed to screen and verify key differences in gut genes between WT and TLR4-KO mice. Functional study of core dysregulated factors was performed in intestinal cell lines.Results: We found that DSS-induced intestinal injury was aggravated by LPS (TLR4 agonist) and TLR4-KO. When compared to WT mice, IL6, CCL2, CSF3, IL11, Ccnb1, Ccnd1 and TNF-alpha significantly decreased and Fas and FasL have increased in the gut of TLR4-KO mice. IL6, CCL2, CSF3, Fas and FasL have all increased in CT-26 cells treated with LPS. Combined with the above data and KEGG enrichment, it can be assumed that TLR4-KO might aggravate DSS-induced intestinal damage by attenuating cell cycle, cytokine-cytokine receptor interaction, and Toll-like receptor signaling pathway, and enhancing the apoptosis pathway. In the functional study of core dysregulated factors, it was found that LPS, IL6, IL11, CSF3, CCL2, S100A8, S100A9 and Mmp3 have improved viability of colon cancer cell lines and decreased apoptosis rate of mouse colon cancer cells when these were treated with DSS. However, Jo-2 (Fas agonistic monoclonal antibody) played the opposite role in colon cancer cells treated with DSS.Conclusions: TLR4 had a repairing effect on DSS-induced intestinal damage and it up-regulate IL6, CCL2 and CSF3. Fas and FasL enhanced DSS-induced colon injury in mice, but might have little to do with TLR4 signaling.