Intestinal Inflammation: Signaling proteins and the rate of PMN transmigration

摘要 我们小组和其他人最近的报告强调了先天的有益和有害的性质 免疫细胞与肠上皮细胞的相互作用。事实上，正如在炎症性肠病(IBD)中观察到的那样， 过度的炎症反应不仅导致粘膜损伤，而且不利于伤口的修复。我们 现在开始认识到，肠道创伤修复在一定程度上是由共同的受体调节的 在白细胞和肠上皮细胞(IEC)上均有表达。我们最近确定， 广泛表达的膜蛋白CD47是调控黏膜创面愈合所必需的。 肠道和我们目前的数据表明CD47在中性粒细胞(PMN)募集和IEC中都有作用 迁移。我们的初步数据表明，CD47缺陷的IECS和PMN表达较少的血栓反应蛋白-1 (TSP1)，CD47的可溶性配体，促进PMN向损伤的粘膜募集。PMN，作为第一个 反应者也分泌白三烯B4(LTB4)，与其在PMN上表达的高亲和力受体BLT1结合 并扩大了他们的招募。有趣的是，我们最近发现IECS也表达BLT1及其连接，通过 LTB4促进粘膜创面修复。在本项目中，LTB4和TSP1分别作为配体进行评估 在肠道的炎症和修复过程中，中性粒细胞和内皮细胞上的受体表达。我们将在我们的 初步数据和之前的研究有助于我们了解调控机制 炎性条件下黏膜伤口修复，如IBD所见。这些研究不仅将带来新的曙光 肠黏膜组织中炎性细胞与上皮细胞的复杂相互作用 健康和疾病中的损伤/修复，但可能为促进伤口修复的药物靶点提供新的想法 在粘膜发炎期间。

Abstract Recent reports by our group and others have highlighted the beneficial and detrimental nature of innate immune cell interactions with intestinal epithelia. Indeed, as observed in Inflammatory Bowel Disease (IBD), an excessive inflammatory response not only results in mucosal injury but is also detrimental for wound repair. We are now beginning to appreciate that intestinal wound repair is regulated, in part, by common receptors expressed on both leukocytes and intestinal epithelial cells (IECs). We recently determined that the ubiquitously expressed membrane protein CD47 is necessary for regulating mucosal wound healing in the intestine and our current data indicates a role for CD47 in both neutrophil (PMN) recruitment and IEC migration. Our preliminary data suggests that CD47-deficient IECs and PMN express less thrombospondin-1 (TSP1), a soluble ligand for CD47, which promotes PMN recruitment to injured mucosa. PMNs, as the first responders, also secrete Leukotriene B4 (LTB4) that binds to its high affinity receptor BLT1 expressed on PMN and amplifies their recruitment. Interestingly, we recently found that IECs also express BLT1 and its ligation by LTB4 promotes mucosal wound repair. In this project, LTB4 and TSP1 are separately evaluated as ligands for receptors expressed on PMNs and IECs during inflammation and repair in the gut. We will build on our preliminary data and previous studies to move toward our goal of understanding mechanisms regulating mucosal wound repair under inflammatory conditions as seen in IBD. These studies will not only shed new light on the complex interplay between inflammatory cells and epithelial cells in orchestrating intestinal mucosal injury/repair in health and disease but may provide new ideas for druggable targets to promote wound repair during mucosal inflammation.