Control of Neutrophilic Inflammation in Intestinal Health and Disease

总结： 这项建议的主要目的是了解中性粒细胞如何迁移通过肠道 上皮细胞，朝着在病理条件下操纵这一过程的最终目标， 在特发性炎症性肠病的情况下， 肠道细菌感染特别是，结肠炎的发生和严重程度似乎与 随着嗜中性粒细胞穿过结肠上皮的迁移程度的增加， 表明中性粒细胞的迁移可以刺激其他细胞的迁移，从而介导炎症。 因此，嗜中性粒细胞跨上皮迁移和在粘膜表面的积聚是 许多炎症性疾病，这一过程与临床疾病活动直接相关 和上皮损伤。目前，定义嗜中性粒细胞-上皮细胞相互作用的机制 在炎症反应中的作用还不完全清楚。为了填补这一知识空白，我们 已经独特地表明，类花生酸肝氧素A3（HxA 3）通过顶端分泌， 被称为MRP-2的表达的外排泵建立了跨细胞的趋化梯度。 肠上皮细胞，其是嗜中性粒细胞从粘膜下层空间移动到肠上皮细胞所必需的。 炎症时的结肠腔。此外，我们确定了N-酰基乙醇胺（NAE） 这类eCB在抑制中性粒细胞跨上皮迁移中起作用，并且这些 分子通过称为P-糖蛋白（P-gp）的顶端流出泵分泌。我们 假设这些促炎和抗炎途径相互沟通， 反应性，综合机制，以控制炎症状态，这些都是失调 in disease疾病settings设置.为了验证这一中心假设，我们的目标是鉴定HxA 3受体， 中性粒细胞的细胞表面（目的1），确定NAE型ECBs/P-gp和HxA 3/MRP 2的性质 信号（目标2），并探讨这两个途径之间的串扰点，驱动 中性粒细胞的炎症功能（目的3）。这些目标的成功实现将提供一个 控制中性粒细胞穿过肠道迁移的机制的统一图片 这将导致新的生物学原理和治疗干预策略。

Summary: The main objective of this proposal is to understand how neutrophils migrate across the intestinal epithelia, toward the eventual goal of manipulating this process in pathologic conditions where it can become excessive as in the context of idiopathic inflammatory intestinal disease as well as enteric bacterial infection. In particular, occurrence and severity of colitis appears to be correlated with the extent of neutrophil transmigration across the colonic epithelium and recent studies have shown that neutrophil migration can incite the migration of other cells that mediate inflammation. Thus, neutrophil transepithelial migration and accumulation at mucosal surfaces is a hallmark of many inflammatory conditions, and this process correlates directly with clinical disease activity and epithelial injury. Currently, the mechanisms that define neutrophil-epithelial interactions during an inflammatory response are not completely understood. To fill this gap in knowledge, we have uniquely shown that secretion of the eicosanoid hepoxilin A3 (HxA3) through the apically expressed efflux pump known as MRP-2 establishes the chemotactic gradient across the intestinal epithelium that is required for neutrophils from the submucosal space to move into the colonic lumen at times of inflammation. Additionally, we identified the N-acyl ethanolamine (NAE) class of eCBs to function in suppressing neutrophil transepithelial migration, and that these molecules are secreted through the apical efflux pump known as P-glycoprotein (P-gp). We hypothesize that these pro- and anti-inflammatory pathways communicate to provide a responsive, integrated mechanism to control inflammation status and that these are dysregulated in disease settings. To test this central hypothesis, we aim to identify the HxA3 receptor(s) on the cell surface of neutrophils (Aim 1), determine the nature of NAE-type ECBs/P-gp and HxA3/MRP2 signaling (Aim 2), and to explore crosstalk points between these two pathways that drive the inflammatory function of neutrophils (Aim 3). Successful completion of these Aims will provide a consolidated picture of mechanisms controlling neutrophil transmigration across the intestinal epithelium that will lead to both novel biological principles and therapeutic intervention strategies.