Between vigilance and tolerance: Innate immune signaling at the intestinal epithelium

只有一层上皮细胞将密集定植和暴露在环境中的肠腔与大部分无菌的上皮下组织分开。与覆盖的粘液和上皮下粘膜免疫系统一起，上皮已经进化到在肠道微生物群存在的情况下保持稳态。另一方面，在肠致病性细菌感染的情况下，它提供了快速有效的抗微生物宿主防御。越来越多的证据表明，体内平衡和抗微生物宿主防御都依赖于由toll样受体（TLR）、Nod样受体（NLR）或解旋酶等先天免疫受体诱导的上皮信号通路。然而，先天免疫受体配体同样由共生细菌和肠致病性细菌产生，在肠道微生物群存在的情况下，预防炎症和促进体内平衡信号的机制，但在微生物感染的情况下允许快速免疫激活的机制仍然不明确。目前的研究应用旨在更好地理解上皮先天免疫识别，肠道抗菌宿主防御和粘膜稳态的分子过程，特别强调胎儿-产后过渡和调节上皮宿主-微生物相互作用的分子过程。该研究项目涉及以下三个问题：(i)出生后上皮耐受的修饰因子和下游效应的表征。（ii）确定先天免疫识别和成人上皮信号传导的负调控机制。（iii）分析瞬时攻击后终止促炎先天免疫信号的分子过程。该结果有望促进更好地理解建立和维持肠粘膜屏障的过程，并预防症状性粘膜疾病（如炎症性肠病（IBD）或坏死性小肠结肠炎（NEC））的发展。

Only one single layer of epithelial cells separates the densely colonized and environmentally exposed intestinal lumen from the largely sterile subepithelial tissue. Together with the overlaying mucus and the subepithelial mucosal immune system the epithelium has evolved to maintain homeostasis in the presence of the enteric microbiota. On the other hand, it provides rapid and efficient antimicrobial host defence in the event of infection with enteropathogenic bacteria. Increasing evidence suggests that both, homeostasis and antimicrobial host defence rely on epithelial signaling pathways induced by innate immune receptors such as Toll-like receptors (TLR), Nod like receptors (NLR) or helicases. However, innate immune receptor ligands are similarly produced by commensal and enteropathogenic bacteria and the mechanisms that prevent inflammation and facilitate homeostatic signaling in the presence of the enteric microbiota but allow rapid immune activation in the event of microbial infection are still ill-defined. The present research application aims at a better understanding of the molecular processes underlying epithelial innate immune recognition, enteric antimicrobial host defence and mucosal homeostasis with particular emphasis on the fetal-postnatal transition and the molecular processes that regulate the epithelial host-microbial interaction. The research project addresses the following three issues:(i) Characterization of modifying factors and downstream effects of postnatal epithelial tolerance. (ii) Identification of negative regulatory mechanisms of innate immune recognition and signaling at the adult epithelium.(iii) Analysis of the molecular processes that terminate pro-inflammatory innate immune signaling after transient challenge.The results are expected to facilitate a better understanding of the processes involved to establish and maintain the intestinal mucosal barrier and prevent the development of symptomatic mucosal disease such as inflammatory bowel disease (IBD) or necrotizing enterocolitis (NEC).