The role of neuro-immune synapse in macrophage migration

项目摘要 自主神经系统对炎症发展的贡献是一个重要的 具有巨大临床应用潜力的新课题。已证实α7烟碱 乙酰胆碱受体（α 7 nAChR）是抗炎胆碱能途径的关键组分， 在感染、关节炎、糖尿病和动脉粥样硬化期间保护生物体。到目前为止， α 7 nAChR仅建立在抑制促炎细胞因子如TNFα表达的基础上 和IL-6然而，α 7 nAChR参与炎症反应的机制似乎更多地是由于α 7 nAChR的表达水平与炎症反应有关。 全面。炎症反应的最关键步骤之一是巨噬细胞迁移到 炎症部位。本课题的目的是研究巨噬细胞迁移调控的机制 由自主神经系统控制。我们假设α 7 nAChR激活影响巨噬细胞迁移 在炎症过程中，通过改变细胞粘附受体的表达，从而改变整个α 7 nAChR- 介导的抗炎反应。在强有力的初步数据的指导下，这一假设将得到检验， 有三个具体目标：1。确定α 7 nAChR对巨噬细胞蓄积的贡献， 利用体内炎症模型的炎症部位。2.评价α 7 nAChR对 巨噬细胞粘附和迁移。3.定义调节的关键分子 α 7 nAChR介导的白细胞迁移。在第一个目标下，α 7 nAChR缺陷对 评价内毒素血症和动脉粥样硬化期间的巨噬细胞积聚。在第二个目标下， 将使用体外粘附和迁移试验评估α 7 nAChR对巨噬细胞运动性的贡献。 在第三个目标下，巨噬细胞上粘附和趋化因子受体的α 7 nAChR依赖性表达 将进行评估和分析。我们的研究的意义在于提供了一个新的见解， 炎症过程中神经免疫突触的功能。α 7 nAChR胆碱能的直接作用 受体向单核细胞/巨噬细胞迁移提出了一种新的炎症调节机制， 通过迷走神经的反应。这项建议是创新的，因为大多数研究胆碱能抗- 炎症机制集中在烟碱激动剂抑制炎症介质的合成和释放的能力上 来自激活的巨噬细胞的炎症细胞因子。我们提出神经免疫突触在 巨噬细胞迁移我们的研究结果将提供关于 炎症中的α 7 nAChR。这些发现对于靶向α 7 nAChR以 调节巨噬细胞迁移和控制几种疾病中的炎症。发展反 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.