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

只有单层上皮细胞将密集定植和暴露于环境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，上皮已经进化为在肠道微生物群存在下维持稳态。另一方面，在感染肠道致病菌的情况下，它提供快速和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先天免疫受体如Toll样受体（TLR）、Nod样受体（NLR）或解旋酶诱导的上皮信号传导途径。然而，先天免疫受体配体类似地由肠道和肠道致病性细菌产生，并且在肠道微生物群存在下预防炎症和促进稳态信号传导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。本研究应用旨在更好地了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-出生后的过渡和调节上皮宿主-微生物相互作用的分子过程。该研究项目解决了以下三个问题：（一）修饰因子的表征和出生后上皮耐受的下游效应。(ii)成人上皮先天免疫识别和信号传导的负调控机制的鉴定。(iii)对瞬时激发后终止促炎性先天免疫信号传导的分子过程的分析。预计结果将有助于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).