Formyl peptide receptors as mediators of intestinal mucosal homeostasis

描述(申请人提供)：胃肠道上皮起着动态屏障的作用，作为管腔内容物和底层组织间隔之间的接口，因此对维持粘膜内环境的稳定至关重要。在肠道感染、炎症性肠病和缺血性损伤后可观察到粘膜损伤。关键的上皮屏障的破坏允许腔内容物进入免疫特异室，从而促进疾病的发病。作为对损伤的反应，肠上皮细胞(IEC)迁移和增殖以快速覆盖裸露表面并重建上皮屏障。我们最近发现N-甲酰肽受体(FPR1和FPR2)在肠上皮细胞中表达。我们的研究确定，细菌衍生的N-甲酰肽FMLF和内源性Annexin 1蛋白是FPR家族成员的激动剂，它们促进肠上皮细胞迁移并促进伤口闭合。此外，越来越明显的是，健康的优化肠道菌群在正常的肠道内稳态和粘膜损伤的恢复中起着重要的作用。我们实验室最近的实验结果表明，暴露于FMLF和完整细菌的上皮细胞也迅速启动细胞质信号转导事件，激活RAC和CDC2，产生活性氧(ROS)，上皮细胞迁移和伤口闭合。因此，我们认为FPR是肠上皮细胞中重要的新型模式识别受体(PRR)，它传递动态平衡信号并促进病理损伤后上皮屏障的恢复。因此，我们的总体目标是确定上皮FPR和微生物区系在调节肠道内稳态、屏障恢复和消退炎症方面的病理生物学功能。

DESCRIPTION (provided by applicant): The gastrointestinal epithelium functions as a dynamic barrier that serves as an interface between luminal contents and underlying tissue compartments, and is thus vital in maintaining mucosal homeostasis. Mucosal wounds have been observed following enteric infection, inflammatory bowel disease and ischemic insults. Disruption of the critical epithelial barrier allows access of luminal contents to immunologically privileged compartments thereby contributing to disease pathogenesis. In response to injury, intestinal epithelial cells (IEC) migrate and proliferate to rapidly cover denuded surfaces and re-establish the epithelia barrier. We have recently identified expression of the N-formyl peptide receptors (FPR1 and FPR2) in the intestinal epithelium. Our studies determined that a bacterial derived N-formyl peptide, fMLF and the endogenous Annexin 1 protein, which are agonists for FPR family members, promote intestinal epithelial cell migration and facilitate wound closure. Additionally, it is becoming evident that a healthy optimized intestinal microflora mediates important roles in normal gut homeostasis and recovery from mucosal insults. Recent experimental results in our laboratory revealed that epithelial cells exposed to fMLF and intact bacteria also rapidly initiate cytoplasmic signaling events, Rac and Cdc2 activation, reactive oxygen species (ROS) production, epithelial cell migration and wound closure. Thus, we believe that FPRs represent important novel type of pattern recognition receptors (PRR) in the intestinal epithelium that transmit homeostatic signaling and facilitate epithelial barrier recovery following pathologic insults. Thus, our overall objectives are to define the pathobiologic function of epithelial FPRs and microbiota in regulating intestinal homeostasis, barrier recovery and resolution of inflammation.