Critical role of toll-like receptor 4 (TLR4) in dextran sulfate sodium (DSS)-Induced intestinal injury and repair
Critical role of toll-like receptor 4 (TLR4) in dextran sulfate sodium (DSS)-Induced intestinal injury and repair
复制标题
Toll 样受体 4 (TLR4) 在葡聚糖硫酸钠 (DSS) 诱导的肠道损伤和修复中的关键作用
DOI：
10.1016/j.toxlet.2019.08.012
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发表时间：
2019-10-15
影响因子：
3.5
通讯作者：
Wang, Hao
中科院分区：
文献类型：
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作者：
Shi, Yun-Jie;Gong, Hai-Feng;Wang, Hao
溃疡性结肠炎(UC)是一种炎症性肠病(IBD)，会导致人类消化道的长期炎症和溃疡。TLR4在肠上皮细胞中的修复功能尚不清楚。本实验采用野生型(4)(WT)小鼠、TLR4基因敲除小鼠(KO；TLR4(-/-))和共膜耗竭小鼠作为葡聚糖硫酸钠(DSS)诱导或辐射诱导的结肠炎和损伤模型，探讨TLR4信号在肠道损伤中的作用。外源性脂多糖(LPS)促进DSS诱导的炎性细胞因子，加重肠损伤。TLR4缺乏和共生细菌耗竭抑制了内毒素的毒性作用，但这些小鼠更容易受到DSS和辐射诱导的肠道损伤。与WT小鼠相比，DSS和辐射都没有促进TLR4-KO和共生膜耗竭小鼠肠道中更多炎性细胞因子的产生。引入细胞因子修复因子PGE2和GM-CSF，增加了DSS诱导的结肠炎小鼠肠道中的细胞因子水平。我们推测TLR4及其配体通过上调PGE2和GM-CSF来修复DSS和辐射诱导的肠损伤后的肠上皮细胞。Transwell迁移实验表明，内毒素、IL-6、肿瘤坏死因子、前列腺素E(2)和GM-CSF可促进肠道细胞迁移，细胞存活率分析表明这些因素对放射性肠损伤有保护作用。我们的数据强调了TLR4在肠道损伤和修复中平衡作用的重要性。
Ulcerative colitis(2) (UC) is an inflammatory bowel disease(3) (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair function of TLR4 in the intestinal epithelium is still unknown. Here, wild-type(4) (WT) mice, TLR4-knockout mice5 (KO; TLR4(-/-)) and commensal-depleted mice were used as dextran sulfate sodium6 (DSS)-induced or radiation-induced colitis and injury models to explore the role of TLR4 signaling in intestinal injury. Exogenous lipopolysaccharide(7) (LPS) promoted DSS-induced inflammatory cytokines and aggravated intestinal damage. TLR4 deficiency and commensal bacterial depletion inhibited the toxic effects of LPS, but these mice were more susceptible to DSS-induced and radiation-induced intestinal damage. Compared with WT mice, neither DSS nor radiation promoted production of more inflammatory cytokines in the guts of TLR4-KO and commensal-depleted mice. Introducing the cytokine repair factors, PGE2 and GM-CSF, increased the cytokine levels in the guts of DSS-induced colitis mice. We hypothesized that TLR4 and its ligands repaired the epithelium after DSS-induced and radiation-induced intestinal damage by upregulating PGE2 and GM-CSF. Transwell migration assays suggested that LPS, IL6, TNF, PGE(2) and GM-CSF promoted intestinal cell migration, and cell viability analysis suggested that these factors protected against radiation-induced intestinal damage. Our data underscore the importance of the balancing role of TLR4 in intestinal injury and repair.