Formyl peptide receptors as mediators of intestinal mucosal homeostasis

描述（由申请人提供）：胃肠上皮作为动态屏障发挥作用，作为腔内容物和下层组织隔室之间的界面，因此对维持粘膜稳态至关重要。在肠道感染、炎症性肠病和缺血性损伤后观察到粘膜损伤。关键上皮屏障的破坏允许管腔内容物进入免疫特权区室，从而有助于疾病的发病机制。肠上皮细胞（IEC）对损伤的反应是迁移和增殖，以迅速覆盖裸露的表面并重建上皮屏障。我们最近发现的N-甲酰肽受体（FPR 1和FPR 2）在肠上皮细胞的表达。我们的研究确定，细菌衍生的N-甲酰肽，fMLF和内源性膜联蛋白1蛋白，这是FPR家族成员的激动剂，促进肠上皮细胞迁移和促进伤口闭合。此外，越来越明显的是，健康的优化的肠道微生物菌群介导正常肠道稳态和从粘膜损伤中恢复的重要作用。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传导事件，Rac和Cdc 2激活，活性氧（ROS）的产生，上皮细胞迁移和伤口闭合。因此，我们认为FPR代表了肠上皮中重要的新型模式识别受体（PRR），其传递稳态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和微生物群在调节肠内稳态、屏障恢复和炎症消退中的病理生物学功能。

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.