Epithelial-specific blockade of MyD88-dependent pathway causes spontaneous small intestinal inflammation.
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.
Gong
Jianfeng
J
Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China.
Xu
Jingyue
J
Zhu
Weiming
W
Gao
Xiang
X
Li
Ning
N
Li
Jieshou
J
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001419:Bacteria; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007410:Intestinal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D008070:Lipopolysaccharides; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C026615:villin