Epithelial-specific blockade of MyD88-dependent pathway causes spontaneous small intestinal inflammation
Epithelial-specific blockade of MyD88-dependent pathway causes spontaneous small intestinal inflammation
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DOI：
10.1016/j.clim.2010.04.001
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发表时间：
2010-08-01
影响因子：
8.6
通讯作者：
Li, Jieshou
中科院分区：
文献类型：
--
作者：
Gong, Jianfeng;Xu, Jingyue;Li, Jieshou
越来越多的证据表明，Toll样受体（TLR）信号在肠上皮细胞（IEC）水平上的作用，以保护肠道免受外源性损伤或病原性感染。我们假设肠上皮细胞中MyD 88依赖性TLR信号传导对粘膜免疫稳态至关重要。在目前的研究中，产生了转基因小鼠模型，其中MyD 88（dnMyD 88）的显性阴性突变体由肠上皮特异性小鼠绒毛启动子驱动。老年转基因小鼠自发发生慢性小肠炎症，表现为CD 4（+）和CD 8（+）淋巴细胞增加、中性粒细胞和巨噬细胞浸润、TNF-α、IFN-γ、IL-1 β和IL-17等细胞因子产生增加、隐窝肿胀、水肿和杯状细胞耗竭。慢性炎症不是由于上皮细胞凋亡或渗透性增加，而是由于潘氏细胞衍生的α-防御素（cryptdins）和RegIII-γ减少以及肠道细菌易位增加。因此，上皮MyD 88依赖性途径在体内限制粘膜微生物菌群渗透和防止粘膜免疫调节紊乱中起重要作用。(C)2010年爱思唯尔公司All rights reserved.
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-1 beta 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. (C) 2010 Elsevier Inc. All rights reserved.