Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis
Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis
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DOI：
10.1152/ajpgi.00328.2004
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发表时间：
2005-05-01
影响因子：
4.5
通讯作者：
Abreu, MT
中科院分区：
文献类型：
--
作者：
Fukata, M;Michelsen, KS;Abreu, MT
炎症性肠病（IBD）是由对肠道细菌的黏膜免疫反应失调引起的。toll样受体（TLR）4识别LPS并通过适配分子髓样分化标记物88 （MyD88）转导促炎信号。我们假设TLR4参与了对肠道细菌的先天免疫反应和结肠炎的发生。TLR4-/-和MyD88-/-小鼠和同窝对照给予2.5%葡聚糖硫酸钠（DSS） 5或7天，然后7天恢复。结肠炎通过体重减轻、直肠出血和组织病理学进行评估。对巨噬细胞标志物、趋化因子表达和细胞增殖标志物进行免疫染色。与野生型小鼠相比，DSS治疗TLR4-/-小鼠的急性炎症细胞显著减少，尽管上皮损伤程度相似。TLR4-/-小鼠比对照小鼠出血更早、更严重。在MyD88-/-小鼠中也看到了类似的结果，表明这是主要的下游途径。TLR4-/-和MyD88-/-小鼠的肠系膜淋巴结更频繁地生长革兰氏阴性菌。中性粒细胞募集的改变是由于TLR4-/-和MyD88-/-小鼠固有层巨噬细胞的巨噬细胞炎性蛋白-2表达减少。尽管敲除小鼠的上皮细胞增殖减少，但TLR4-/-或MyD88-/-与野生型小鼠的隐窝上皮损伤相似。TLR4通过适配器分子MyD88在肠道损伤反应和限制细菌易位中发挥重要作用。尽管管腔细菌具有多样性，但其他tlr并不能替代TLR4在急性结肠炎模型中的作用。先天免疫反应缺陷可能导致细菌清除率降低，最终导致对正常菌群的反应失调。
Inflammatory bowel disease (IBD) arises from a dysregulated mucosal immune response to luminal bacteria. Toll-like receptor (TLR)4 recognizes LPS and transduces a proinflammatory signal through the adapter molecule myeloid differentiation marker 88 (MyD88). We hypothesized that TLR4 participates in the innate immune response to luminal bacteria and the development of colitis. TLR4-/- and MyD88-/- mice and littermate controls were given 2.5% dextran sodium sulfate (DSS) for 5 or 7 days followed by a 7-day recovery. Colitis was assessed by weight loss, rectal bleeding, and histopathology. Immunostaining was performed for macrophage markers, chemokine expression, and cell proliferation markers. DSS treatment of TLR4-/- mice was associated with striking reduction in acute inflammatory cells compared with wild-type mice despite similar degrees of epithelial injury. TLR4-/- mice experienced earlier and more severe bleeding than control mice. Similar results were seen with MyD88-/- mice, suggesting that this is the dominant downstream pathway. Mesenteric lymph nodes from TLR4-/- and MyD88-/- mice more frequently grew gram-negative bacteria. Altered neutrophil recruitment was due to diminished macrophage inflammatory protein-2 expression by lamina propria macrophages in TLR4-/- and MyD88-/- mice. The similarity in crypt epithelial damage between TLR4-/- or MyD88-/- and wild-type mice was seen despite decreased epithelial proliferation in knockout mice. TLR4 through the adapter molecule MyD88 is important in intestinal response to injury and in limiting bacterial translocation. Despite the diversity of luminal bacteria, other TLRs do not substitute for the role of TLR4 in this acute colitis model. A defective innate immune response may result in diminished bacterial clearance and ultimately dysregulated response to normal flora.