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性免疫缺陷的有益和有害性质。 免疫细胞与肠上皮细胞的相互作用。事实上，如在炎症性肠病（IBD）中所观察到的， 过度的炎症反应不仅导致粘膜损伤，而且对伤口修复也是有害的。我们 现在开始认识到肠道伤口的修复部分是由普通受体调节的， 在白细胞和肠上皮细胞（IEC）上表达。我们最近确定， 普遍表达的膜蛋白CD 47是调节粘膜创伤愈合所必需的。 我们目前的数据表明，CD 47在中性粒细胞（PMN）募集和IEC中的作用 迁移我们的初步数据表明，CD 47缺陷的IEC和PMN表达较少的血小板反应素-1 TSP 1是CD 47的可溶性配体，其促进PMN募集到损伤的粘膜。PMNs作为第一个 应答者也分泌白三烯B4（LTB 4），与PMN上表达的高亲和力受体BLT 1结合 扩大了他们的招募规模有趣的是，我们最近发现IEC也表达BLT 1及其连接， LTB 4促进粘膜创伤修复。在该项目中，LTB 4和TSP 1分别作为配体进行评估， 在炎症和肠道修复过程中，PMNs和IEC上表达的受体。我们将建立在我们的 初步的数据和以前的研究，朝着我们的目标，了解机制调节 炎症条件下的粘膜伤口修复，如IBD中所见。这些研究不仅会为我们 炎症细胞和上皮细胞之间复杂的相互作用， 健康和疾病中的损伤/修复，但可能为促进伤口修复的可药物靶点提供新思路 在粘膜炎症期间。

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.