TRIF Signaling Drives Homeostatic Intestinal Epithelial Antimicrobial Peptide Expression
TRIF Signaling Drives Homeostatic Intestinal Epithelial Antimicrobial Peptide Expression
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DOI：
10.4049/jimmunol.1302708
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发表时间：
2014-10
期刊：
影响因子：
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通讯作者：
Silvia Stockinger;C. Duerr;M. Fulde;Tamas Dolowschiak;J. Pott;I. Yang;D. Eibach;F. Bäckhed;S. Akira
中科院分区：
文献类型：
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作者：
Silvia Stockinger;C. Duerr;M. Fulde;Tamas Dolowschiak;J. Pott;I. Yang;D. Eibach;F. Bäckhed;S. Akira
最近的研究结果表明先天免疫信号对维持粘膜稳态有重要贡献，但确切的潜在信号转导途径尚不明确。通过对从常规饲养的无菌小鼠以及缺乏衔接分子MyD88和TRIF、TLR3和TLR4以及I型和III型IFN受体的动物中分离的肠上皮细胞的比较分析，我们证明了在稳态条件下显著的TLR介导的信号传导。令人惊讶的是，Reg3γ和潘氏细胞肠抗微生物肽的稳态表达严重依赖于TRIF和部分TLR3，但不依赖于IFN受体信号传导。与野生型上皮相比，TRIF突变体中抗菌肽表达减少与潘氏细胞数量显著减少以及潘氏细胞成熟和分化因子表达减少相关。在共饲养期间，该表型未转移至TRIF充足的无菌动物。TRIF缺陷小鼠中的低抗微生物肽表达导致口服给药细菌的立即杀灭减少，但与肠道微生物群整体组成的显著改变无关。在短暂的上皮损伤后，表型以TRIF独立的方式迅速恢复。我们的结果确定TRIF信号传导是维持肠上皮屏障功能的真正稳态途径，揭示了粘膜稳态和组织修复之间先天免疫信号传导的根本差异。
Recent results indicate a significant contribution of innate immune signaling to maintain mucosal homeostasis, but the precise underlying signal transduction pathways are ill-defined. By comparative analysis of intestinal epithelial cells isolated from conventionally raised and germ-free mice, as well as animals deficient in the adaptor molecules MyD88 and TRIF, the TLR3 and TLR4, as well as the type I and III IFN receptors, we demonstrate significant TLR-mediated signaling under homeostatic conditions. Surprisingly, homeostatic expression of Reg3γ and Paneth cell enteric antimicrobial peptides critically relied on TRIF and, in part, TLR3 but was independent of IFN receptor signaling. Reduced antimicrobial peptide expression was associated with significantly lower numbers of Paneth cells and a reduced Paneth cell maturation and differentiation factor expression in TRIF mutant compared with wild-type epithelium. This phenotype was not transferred to TRIF-sufficient germ-free animals during cohousing. Low antimicrobial peptide expression in TRIF-deficient mice caused reduced immediate killing of orally administered bacteria but was not associated with significant alterations in the overall composition of the enteric microbiota. The phenotype was rapidly restored in a TRIF-independent fashion after transient epithelial damage. Our results identify TRIF signaling as a truly homeostatic pathway to maintain intestinal epithelial barrier function revealing fundamental differences in the innate immune signaling between mucosal homeostasis and tissue repair.