Gnotobiotic IL-10-/-;NF-κBEGFP mice reveal the critical role of TLR/NF-κB signaling in commensal bacteria-induced colitis
Gnotobiotic IL-10-/-;NF-κBEGFP mice reveal the critical role of TLR/NF-κB signaling in commensal bacteria-induced colitis
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DOI：
10.4049/jimmunol.178.10.6522
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发表时间：
2007-05-15
影响因子：
4.4
通讯作者：
Jobin, Christian
中科院分区：
文献类型：
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作者：
Karrasch, Thomas;Kim, Joo-Sung;Jobin, Christian
在葡聚糖硫酸钠诱导的肠道损伤中，共生菌和TLR信号与肠道稳态的维持有关。本研究的目的是确定TLR/ nf - κ B激活在共生菌诱导的T细胞介导的结肠炎模型中的体内作用。将NF-kappa B报告基因小鼠（NF-kappa B (EGFP)） （EGFP, enhanced GFP）与结肠炎易感菌株IL-10（-/-）杂交，利用胚胎移植技术获得无菌条件。Gerinfree il - 10 (wt / wt);NF-kappa B-EGFP与IL-10(-/-)；NF-kappa B-EGFP小鼠（野生型，wt）与非致病性粪肠球菌和大肠杆菌双重相关。采用宏观成像、共聚焦显微镜和流式细胞术检测EGFP。il - 10 (- / -);使用MyD88（-/-）小鼠评估粪肠球菌/大肠杆菌。大肠杆菌诱导的tlr依赖性信号和IL-23基因表达。Dual-associated il - 10 (- / -);NF-kappa B （EGFP）小鼠在7周时出现严重炎症。宏观分析显示，EGFP在细菌相关IL-10（-/-）结肠中表达升高；nf - κ B （EGFP）小鼠。共聚焦显微镜分析显示，在细菌定植的早期（1周），IL-10（wt/wt）和IL-10（-/-）小鼠的肠细胞中egfp呈阳性，而在结肠炎（7周）期间，IL-10（-/-）小鼠的信号转向固有层T细胞、树突状细胞、中性粒细胞和巨噬细胞。NF-kappa B抑制剂BAY 11-7085对粪肠球菌/大肠杆菌有减毒作用。大肠杆菌诱导的EGFP表达和结肠炎的发生。此外，E. faecalis/E。大肠杆菌诱导的NF-kappa B信号和IL-23基因表达在IL-10衍生的骨髓来源树突状细胞中被阻断；MyD88(- / -)小鼠。我们得出结论，细菌诱导的实验性结肠炎涉及tlr诱导的nf - κ B信号的激活，这些信号主要来自粘膜免疫细胞。阻断tlr诱导的nf - κ B活性可能是治疗免疫介导的肠道炎症的一种有吸引力的策略。免疫学杂志，2007,18(2):522- 532。
Commensal bacteria and TLR signaling have been associated with the maintenance of intestinal homeostasis in dextran sodium sulfate-induced intestinal injury. The aim of this study was to determine the in vivo role of TLR/NF-kappa B activation in a model of commensal bacteria-induced T cell-mediated colitis. A NF-kappa B reporter gene mouse (NF-kappa B (EGFP)) (EGFP, enhanced GFP) was crossed to the colitogenic susceptible strain IL-10(-/-) and derived into germfree conditions using embryo-transfer technology. Gerinfree IL-10(wt/wt);NF-kappa B-EGFP and IL-10(-/-);NF-kappa B-EGFP mice (wt, wild type) were dual associated with the nonpathogenic commensal bacteria strains Enterococcus faecalis and Escherichia coli. EGFP was detected using macroimaging, confocal microscopy, and flow cytometry. IL-10(-/-);MyD88(-/-) mice were used to assess E.faecalis/E. coli-induced TLR-dependent signaling and IL-23 gene expression. Dual-associated IL-10(-/-);NF-kappa B (EGFP) mice developed severe inflammation by 7 wk. Macroscopic analysis showed elevated EGFP expression throughout the colon of bacteria-associated IL-10(-/-);NF-kappa B (EGFP) mice. Confocal microscopy analysis revealed EGFP-positive enterocytes during the early phase of bacterial colonization (1 wk) in both IL-10(wt/wt) and IL10(-/-) mice, while the signal shifted toward lamina propria T cells, dendritic cells, neutrophils, and macrophages in IL-10(-/-) mice during colitis (7 wk). The NF-kappa B inhibitor BAY 11-7085 attenuated E. faecalis/E. coli-induced EGFP expression and development of colitis. Additionally, E. faecalis/E. coli-induced NF-kappa B signaling and IL-23 gene expression were blocked in bone marrowderived dendritic cells derived from IL-10(-/-);MyD88(-/-) mice. We conclude that bacteria-induced experimental colitis involves the activation of TLR-induced NF-kappa B signaling derived mostly from mucosal immune cells. Blocking TLR-induced NF-kappa B activity may represent an attractive strategy to treat immune-mediated intestinal inflammation. The Journal of Immunology, 2007, 178: 6522-6532.