Neutrophils instruct macrophage responses to promote mucosal healing

项目摘要/摘要 粘膜愈合被认为是胃肠道疾病的重要临床终点，包括 炎症性肠病(IBD)。因此，它是开发旨在实现以下目标的治疗方法的一个有吸引力的目标 持续的临床缓解。肠粘膜中性粒细胞的存在通常与疾病的严重程度有关。 然而，在组织损伤方面，PMN在消解炎症方面的贡献越来越得到认可。因此， 虽然我们对中性粒细胞是终末分化的吞噬细胞促进组织损伤的观点正在改变， PMN有益作用的潜在机制仍然知之甚少。同样，尽管巨噬细胞 (Mϕ)对增强肠道免疫反应和消退炎症有很好的贡献 公认的、指导其效应器功能的分子线索仍有待定义。 我们正在进行的研究表明，组织中性粒细胞对消炎有一种新的有益的贡献。 和粘膜损伤。我们已经确定了几种新的机制和新的分子角色，通过这些机制和新的分子角色 指导活动性肠炎MϕS促进粘膜愈合。我们发现PMN胞外 囊泡(EVS)介导调节性微RNA(MiRNAs)和促修复因子(如转化生长因子-1)的局部转移 β1)，它们分别通过平行活动抑制炎症和促进修复细胞因子 在肠道MϕS中表达。我们还发现了一种新的调节功能， 细胞间黏附分子-1，在调节M-ϕ的泡腾吞噬活性中起作用。细胞间黏附分子-1在M-ϕ激活过程中高度上调(其表达 仅限于炎症性M-ϕ(S)，当与中性粒细胞结合时，关键调节 损伤组织中的凋亡/坏死性上皮细胞。 因此，这项提案的总体目标是测试一种新的概念，即组织浸润性PMN有助于 重编程肠道MϕS促进损伤肠粘膜炎症消退 拟议的实验将使用最先进的成像技术，强大的体内损伤模型与 创新的分子和生化方法：1.确定中性粒细胞-巨噬细胞ϕ相互作用如何促进损伤 在肠粘膜中的分解。2.确定PMN-EVS如何增强炎症的促修复活性 创伤MϕS和3.确定中性粒细胞结合和细胞间黏附分子-1信号在创伤MϕS调节泡腾和 促进伤口清创。 我们的研究将确定新的机制，管理损伤的粘膜和他们的天然免疫细胞的相互作用 在解决伤害中的作用。

Project Summary/Abstract Mucosal healing is considered an important clinical end-point of gastrointestinal disorders, including inflammatory bowel diseases (IBD). As such, it is an attractive target for developing therapies aimed at achieving sustained clinical remission. PMN presence in the intestinal mucosa is often associated with disease severity and tissue damage, however, PMN contributions to resolution of inflammation are increasingly recognized. Thus, while our view of PMNs as terminally differentiated phagocytes that promote tissue damage is changing, mechanisms underlying beneficial roles of PMNs remain poorly understood. Likewise, although macrophage (Mϕ) contributions to mounting immune responses in the gut and to resolution of inflammation are well recognized, molecular cues that instruct their effector functions remain to be defined. Our ongoing studies indicate a novel and beneficial contribution of tissue PMNs to the resolution of inflammation and mucosal injury. We have identified several novel mechanisms and new molecular players by which PMNs instruct the activity of inflammatory gut Mϕs to promote mucosal healing. We found that PMN extracellular vesicles (EVs) mediate localized transfer of regulatory micro-RNAs (miRNAs) and pro-repair factors (e.g. TGF- β1), which respectively, through parallel activity suppress inflammatory and promote pro-repair cytokine expression in gut Mϕs. We also identified a new regulatory role for a well-characterized PMN adhesion ligand, ICAM-1, in regulating Mϕ efferocytotic activity. ICAM-1 is highly upregulated during Mϕ activation (its expression is restricted to inflammatory Mϕs) and when ligated by PMN binding, critically regulates clearance of apoptotic/necrotic epithelial cells in injured tissue. Therefore, the overall goal of this proposal is to test a novel concept whereby tissue infiltrating PMNs facilitate reprogramming of gut Mϕs to promote inflammatory resolution of the injured intestinal mucosa. Proposed experiments will use state of the art imaging techniques, powerful in vivo injury models combined with innovative molecular and biochemical approaches to: 1. Determine how PMN-Mϕ interactions facilitate injury resolution in the intestinal mucosa. 2. Determine how PMN-EVs enhance the pro-repair activity of inflammatory wound Mϕs and 3. Determine how PMN binding and ICAM-1 signaling in wound Mϕs regulate efferocytosis and facilitate wound debridement. Our studies will define new mechanisms governing innate immune cell interactions in wounded mucosa and their function in injury resolution.