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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要自主神经系统对炎症发展的贡献是重要的 α7烟碱具有巨大的临床应用潜力。乙酰胆碱受体 (α7nAChR) 是抗炎胆碱能通路的重要组成部分，迄今为止，在感染、关节炎、糖尿病和动脉粥样硬化期间保护有机体。 α7nAChR 的建立仅是为了预防促炎细胞因子（例如 TNFα）的表达然而，α7nAChR 对炎症反应的贡献机制似乎更多。炎症反应最关键的步骤之一是巨噬细胞迁移到周围。该项目的目标是确定巨噬细胞迁移的调节机制。我们勇敢地承认 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，从而改变整体 α7nAChR- 在强有力的初步数据的指导下，这一假设将得到检验。追求三个具体目标： 1. 确定 α7nAChR 对体内巨噬细胞积累的贡献体内炎症模型的利用部位2.评估α7nAChR对炎症的影响。使用体外测定的巨噬细胞粘附和迁移 3. 定义调节的关键分子。 α7nAChR 介导的白细胞迁移。在第一个目标下，α7nAChR 缺陷对白细胞迁移的影响。将评估内毒素血症和动脉粥样硬化期间的巨噬细胞积累。将使用体外粘附和迁移测定来评估 α7nAChR 对巨噬细胞运动的贡献。第三个目标是巨噬细胞上α7nAChR依赖性粘附和趋化因子受体的表达我们的研究的意义在于提供新的见解。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/巨噬细胞迁移受体提出了炎症调节的新机制这个提议是创新的，因为大多数研究都是针对胆碱能抗药。炎症机制集中于烟碱激动剂抑制合成和释放的能力我们提出了神经免疫突触在激活巨噬细胞中的炎症细胞因子的作用。我们的研究结果将提供有关巨噬细胞迁移作用的全新信息。 α7nAChR 在炎症中的作用对于靶向 α7nAChR 具有重要的治疗意义。调节巨噬细胞迁移并控制多种疾病中的炎症。炎症治疗是我们进一步研究的目标。