The role of neuro-immune synapse in macrophage migration

神经免疫突触在巨噬细胞迁移中的作用

• 批准号: 10359594
• 负责人: Valentin P Yakubenko
• 金额: $ 43.95万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359594
• 关键词: 3-Dimensional; Actins; Adhesions; Adhesives; Adoptive Transfer; Affect; Anti-Cholinergics; Anti-Inflammatory Agents; Apolipoprotein E; Apoptosis; Arthritis; Atherosclerosis; Attenuated; Autonomic nervous system; Blood Circulation; Cell Adhesion Molecules; Cell physiology; Cells; Cholinergic Receptors; Complex; Cytoskeleton; Data; Defense Mechanisms; Development; Diabetes Mellitus; Disease; Endotoxemia; Equilibrium; Extracellular Matrix; Fibrin; Goals; Immune; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Investigation; Label; Lead; Leukocytes; Ligands; Link; Lymphocyte; Mediating; Microfilaments; Migration Assay; Mission; Modeling; Mus; NF-kappa B; Nerve; Neuroimmune; Neurons; Nicotinic Agonists; Organism; Outcome; Pathologic; Pathway interactions; Peptide Hydrolases; Phenotype; Physiological; Play; Prevention; Reactive Oxygen Species; Regulation; Research; Resolution; Role; Sepsis; Signal Pathway; Signal Transduction; Site; Surface; Synapses; TNF gene; Testing; Therapeutic; Tissues; United States National Institutes of Health; Vagus nerve structure; adhesion receptor; alpha-bungarotoxin receptor; base; cell motility; chemokine receptor; cholinergic; clinical application; comparative; cytokine; design; experimental study; in vitro Assay; in vivo; innovation; insight; interest; macrophage; migration; monocyte; novel; novel therapeutics; prevent; protective effect; receptor; recruit; response

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.

项目摘要 自主神经系统对感染发展的贡献是重要的 在临床应用中具有巨大潜力的新主题。已经证明α7烟碱 乙酰胆碱受体（α7NACHR）是抗炎胆碱能途径的关键组成部分 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，受保护的作用 α7NACHR仅在预防促炎细胞因子的表达上建立，例如TNFα 和IL-6。但是，α7NACHR对炎症反应的贡献似乎更多 综合的。炎症反应最关键的步骤之一是巨噬细胞迁移到 炎症部位。该项目的目的是确定受调节巨噬细胞迁移的机制 由自主神经系统。我们假设α7NACHR激活会影响巨噬细胞的迁移 在炎症过程中，通过改变细胞粘附受体的表达，这修改了总体α7nACHR- 介导的抗炎反应。在强大的初步数据的指导下，该假设将通过 追求三个具体目的：1。确定α7nAChR对巨噬细胞积累的贡献 利用体内炎症模型的炎症部位。 2。评估α7NACHR对 巨噬细胞粘合剂和使用体外测定法迁移。 3。定义调节的临界分子 α7NACHR介导的白细胞迁移。在第一个目标下，α7nAChR缺陷对 将评估内毒素血症和动脉粥样硬化期间的巨噬细胞积累。在第二个目标下， α7NACHR对巨噬细胞运动的贡献将使用体外粘附和迁移分析进行评估。 在第三个目标下，巨噬细胞上粘合剂和趋化因子受体的α7NACHR依赖性表达 将进行评估和分析。我们研究的意义在于提供对 炎症过程中神经免疫突触的功能。 α7NACHR胆碱能的直接贡献 单核细胞/巨噬细胞迁移的受体提案提出一种调节炎症的新机制 反应虽然迷走神经。该提议具有创新性，因为大多数胆碱能抗的研究 炎症机制集中在烟碱激动剂抑制合成和释放的能力上 活化巨噬细胞的炎性细胞因子。我们提出了神经免疫突触在 巨噬细胞迁移。我们的研究结果将提供有关有关作用的全新信息 炎症中的α7NACHR。这些发现将靶向α7NACHR靶向α7NACHR将具有显着的治疗兴趣 调节多种疾病的巨噬细胞迁移并控制注射。反 - 的发展 炎症治疗是我们进一步研究的目标。