Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China.
Clin Immunol. 2010 Aug;136(2):245-56. doi: 10.1016/j.clim.2010.04.001. Epub 2010 May 8.
Accumulating evidence suggests a role for Toll-like receptor (TLR) signaling at the intestinal epithelial cells (IECs) level for intestinal protection against exogenous injury or pathogenic infection. We hypothesized that MyD88 dependent TLR signaling at intestinal epithelium is critical for mucosal immune homeostasis. In the current study, a transgenic mouse model was generated in which a dominant-negative mutant of MyD88 (dnMyD88) was driven by an intestinal epithelial-specific murine villin promoter. Aged transgenic mice spontaneously developed chronic small intestinal inflammation, as revealed by increased CD4+ and CD8+ lymphocytes, neutrophil and macrophage infiltration, increased production of cytokines as TNF-alpha, IFN-gamma, IL-1beta, and IL-17, crypt abscesses, lymphedema, and Goblet cell depletion. The chronic inflammation was not due to increased epithelial apoptosis or permeability, but to a decreased Paneth cell-derived alpha-defensins (cryptdins) and RegIII-gamma and increased commensal bacteria translocation. Thus, epithelial MyD88-dependent pathway plays an essential role in limiting mucosal microflora penetration and preventing mucosal immunoregulation disturbance in vivo.
越来越多的证据表明，Toll 样受体 (TLR) 信号在肠道上皮细胞 (IEC) 水平上对于肠道对外源性损伤或病原感染的保护作用。我们假设肠道上皮细胞中 MyD88 依赖性 TLR 信号对于黏膜免疫稳态至关重要。在本研究中，我们构建了一种转基因小鼠模型，该模型中 MyD88 的显性负突变体 (dnMyD88) 由肠道上皮细胞特异性的鼠微绒毛蛋白启动子驱动。年龄较大的转基因小鼠自发地发展为慢性小肠炎症，表现为 CD4+和 CD8+淋巴细胞、中性粒细胞和巨噬细胞浸润增加，TNF-α、IFN-γ、IL-1β和 IL-17 等细胞因子的产生增加，隐窝脓肿，淋巴水肿和杯状细胞耗竭。这种慢性炎症不是由于上皮细胞凋亡或通透性增加引起的，而是由于 Paneth 细胞衍生的α-防御素（cryptdins）和 RegIII-γ减少以及共生细菌易位增加所致。因此，上皮细胞 MyD88 依赖性途径在限制黏膜微生物群穿透和防止体内黏膜免疫调节紊乱方面发挥着重要作用。
