The role of neuro-immune synapse in macrophage migration

项目总结 自主神经系统在炎症发展中的作用是一个重要的 具有巨大临床应用潜力的新课题。已经证明，α7尼古丁 乙酰胆碱受体(α7nAChR)是抗炎胆碱能途径的重要组成部分 在感染、关节炎、糖尿病和动脉粥样硬化期间保护机体。到目前为止，它的保护作用 α7nAChR仅建立在阻止促炎细胞因子的表达上，如肿瘤坏死因子α 和IL-6。然而，α7nAChR在炎症反应中的作用机制似乎更多 全面性。炎症反应最关键的步骤之一是巨噬细胞迁移到 发炎部位。本项目的目标是确定巨噬细胞迁移调节的机制。 通过自主神经系统。我们假设α7nAChR激活影响巨噬细胞迁移 在炎症过程中，通过改变细胞黏附受体的表达，从而改变整个α7nAChR- 介导的抗炎反应。在强劲的初步数据的指导下，这一假设将得到以下检验 追求三个特定目标：1.确定α7nAChR对巨噬细胞在体内聚集的贡献 利用活体炎症模型的炎症部位。2.评价α7nAChR对血管紧张素转换酶活性的影响 巨噬细胞黏附和迁移的体外检测。3.定义调控的关键分子 α7nAChR介导的白细胞迁移。在第一个目标下，α7nAChR缺陷对血管紧张素转换酶活性的影响 将评估内毒素血症和动脉粥样硬化期间巨噬细胞的堆积。在第二个目标下， α7nAChR对巨噬细胞运动的贡献将通过体外黏附和迁移实验来评估。 在第三个目标下，α7nAChR依赖的巨噬细胞黏附和趋化因子受体的表达 将被评估和分析。我们研究的意义在于为我们提供了一个新的视角 炎症过程中神经免疫突触的功能。α7nAChR胆碱能的直接作用 受体向单核/巨噬细胞迁移提出了一种新的炎症调控机制 通过迷走神经的反应。这一建议是创新的，因为大多数胆碱能抗肿瘤的研究 炎症机制主要集中在尼古丁激动剂抑制合成和释放的能力上。 来自激活的巨噬细胞的炎性细胞因子。我们认为神经免疫突触在 巨噬细胞迁移。我们的研究结果将提供关于 α7nAChR参与炎症反应。这些发现将对靶向α7nAChR至 调节巨噬细胞的移动，控制几种疾病中的炎症。反病毒药物的发展 炎症治疗是我们进一步研究的目标。

PROJECT SUMMARY The contribution of the autonomic nervous system to the development of inflammation is an important new subject that has massive potential for clinical applications. It has been demonstrated that α7 nicotinic acetylcholine receptor (α7nAChR) is a critical component of anti-inflammatory cholinergic pathway that protects an organism during infection, arthritis, diabetes and atherosclerosis. So far, the protective role of α7nAChR was established only on the prevention of expression of pro-inflammatory cytokines, such as TNFα and IL-6. However, the mechanism of α7nAChR contribution to inflammatory response seems to be more comprehensive. One of the most critical steps of the inflammatory response is macrophage migration to the site of inflammation. The goal of this project is to determine the mechanism of macrophage migration regulated by the autonomic nervous system. We hypothesize that α7nAChR activation affects macrophage migration during inflammation by changing the expression of cell adhesive receptors, that modifies the overall α7nAChR- mediated anti-inflammatory response. Guided by strong preliminary data, this hypothesis will be tested by pursuing three Specific Aims: 1. Determine the contribution of α7nAChR to macrophage accumulation within the site of inflammation utilizing in vivo inflammatory models. 2. Evaluate the effect of α7nAChR on macrophage adhesion and migration using in vitro assays. 3. Define the critical molecules that regulate α7nAChR-mediated leukocyte migration. Under the first aim, the effect of α7nAChR-deficientcy on macrophage accumulation during endotoxemia and atherosclerosis will be evaluated. Under the second aim, the contribution of α7nAChR to macrophage motility will be assessed using in vitro adhesion and migration assays. Under the third aim, α7nAChR-dependent expression of adhesion and chemokine receptors on macrophages will be evaluated and analyzed. The significance of our study resides in providing a new insight into the function of neuro-immune synapse during inflammation. The direct contribution of α7nAChR cholinergic receptor to monocyte/macrophage migration proposes a new mechanism for the regulation of inflammatory response though the vagus nerve. This proposal is innovative because most studies of cholinergic anti- inflammatory mechanisms have focused on the ability of nicotinic agonists to suppress the synthesis and release of inflammatory cytokines from activated macrophages. We propose the role of neuro-immune synapse in macrophage migration. The results of our studies will provide completely new information regarding the role of α7nAChR in inflammation. These findings will be of significant therapeutic interest for targeting α7nAChR to regulate macrophage migration and to control inflammation in several disorders. The development of anti- inflammatory treatments is an objective of our further investigations.