The impact of Aryl hydrocarbon receptor signaling on Toll like receptor-mediated inflammation

芳基碳氢化合物受体信号传导对 Toll 样受体介导的炎症的影响

基本信息

批准号：
10569113
负责人：
CHRISTOPH F A VOGEL
金额：
$ 33.87万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2022-02-09 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569113
关键词：
Affect Antigen-Presenting Cells Aryl Hydrocarbon Receptor Asthma Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Binding Sites Biological Bone Marrow Cell physiology Cells Chronic Disease Communicable Diseases Communication DNA Binding Data Dendritic Cells Development Dioxins Elements Environmental Pollutants Environmental Risk Factor Event Exposure to Future Gene Expression Gene Expression Profiling Genes Genetic Genome Goals Health Human Hypersensitivity IL12A gene Immune Immune System Diseases Immune response Immune system Immunity Immunoglobulin Fragments Immunologic Deficiency Syndromes Immunologic Monitoring Immunomodulators Immunosuppression Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-6 Knockout Mice Lead Ligands Link Location Logic Lymphocyte Macrophage Maps Mediating Methods Modeling Molecular Monitor Mus NF-kappa B Outcome Pathologic Pathway interactions Physiological Play Positron-Emission Tomography Process Proteins REL Protein Radioimmunoconjugate Receptor Activation Receptor Signaling Regulation Regulatory T-Lymphocyte Reporting Repressor Proteins Role Scheme Shock Signal Pathway Signal Transduction Stimulus Surface Antigens T cell differentiation T-Cell Activation T-Lymphocyte Testing Time Tissues Toll-like receptors Toxic Environmental Substances Toxic effect Transcription Repressor Transgenic Mice Work aryl hydrocarbon receptor ligand cell type chromatin immunoprecipitation chronic inflammatory disease cytokine genome-wide analysis immune activation immune system function immunoreaction immunoregulation immunotoxicity in vivo innovation insight molecular targeted therapies monocyte mouse model mutant neutrophil novel overexpression pathogen protein protein interaction receptor recruit response sensor

项目摘要

Project Summary/Abstract The aryl hydrocarbon receptor (AhR) plays an important role in regulating immune responses and exposure to AhR-activating compounds, including environmental toxicants such as dioxins may contribute to the dysregulation of cytokines and the development of immune system disorders. The ligand-dependent activation of AhR can promote differentiation of inflammatory T helper Th17 cells or lead to profound immunosuppression and an increase of regulatory T cells. Significant gaps exist in our understanding of how the AhR regulates the inter- and intracellular communication processes between dendritic cells (DC) and other immune cells on the molecular level, which is of central importance to understanding both physiologic and pathophysiologic immune reactions mediated through AhR. The overall goal of this proposal is to identify the functional role of the AhR and its specific repressor (AhRR) interacting with Toll-like receptor (TLR) and NFkB signaling in controlling function and differentiation of DC and T-cell activation. The reported dysregulation of TLR and NFkB signaling by AhR ligands may be key steps in triggering immune system disorders. The transcriptional repressor of the AhR, the AhRR is implemented in the AhR pathway, although much remains to be elucidated at the level of TLR and NFkB signaling. In transgenic mice overexpressing AhRR we discovered that AhRR is critically involved in regulation of dioxin-induced inflammatory gene expression as well as LPS-mediated inflammatory responses and LPS shock. Thus, the AhRR Tg mice give us the opportunity to recognize how AhRR is involved in the regulation of TLR-mediated responses and other parts of the immune system. Bone-marrow derived DC from genetic mouse models as well as human DC, will be used to investigate how DC are regulated through ligand- induced activation of the AhR and inflammatory signals via TLR/NFkB. A genome-wide identification of AhR/Rel binding sites will be conducted and related to gene expression analysis. Mutants of binding sites will be generated to validate whether a particular binding event is actually required to regulate the expression of target genes. Protein-protein interaction studies will identify the specific interacting domains of AhR and Rel proteins and provide insight into how these interactions impact the functional activity of each protein and the outcome of AhR/NFkB crosstalk. A novel in vivo method to monitor immune responses noninvasively via Positron Emission Tomography (immuno-PET) imaging will be used to ultimately show how AhR ligands modify TLR-mediated recruitment and accumulation of DC, neutrophils, B cells, and T cells in vivo. This study can provide a definite link and mechanism between the exposure to AhR activating compounds and the development of inflammatory chronic diseases. Findings will allow for more clearly defined endpoints to assess the effects and toxicity of AhR activating ligands including environmental pollutants. This study will also provide new concepts for future innovative uses of AhR and AhRR as molecular targets for therapeutic applications in inflammation, infection, and chronic diseases.

项目概要/摘要芳烃受体 (AhR) 在调节免疫反应和暴露于环境中发挥着重要作用 AhR 激活化合物，包括二恶英等环境毒物，可能会导致细胞因子失调和免疫系统疾病的发展。配体依赖性激活 AhR 可以促进炎症辅助性 T Th17 细胞的分化或导致严重的免疫抑制以及调节性 T 细胞的增加。我们对 AhR 如何监管的理解存在重大差距树突状细胞（DC）和其他免疫细胞之间的细胞间和细胞内通讯过程分子水平，这对于理解生理和病理生理免疫至关重要通过 AhR 介导的反应。该提案的总体目标是确定 AhR 的职能角色和其特异性阻遏蛋白 (AhRR) 与 Toll 样受体 (TLR) 和 NFkB 信号传导相互作用以控制功能以及 DC 和 T 细胞激活的分化。据报道，AhR 对 TLR 和 NFkB 信号传导失调配体可能是引发免疫系统疾病的关键步骤。 AhR 的转录抑制因子 AhRR 是在 AhR 途径中实现的，尽管在 TLR 和 NFkB 信号传导。在过度表达 AhRR 的转基因小鼠中，我们发现 AhRR 关键参与二恶英诱导的炎症基因表达以及脂多糖介导的炎症反应的调节和LPS休克。因此，AhRR Tg 小鼠让我们有机会了解 AhRR 如何参与调节 TLR 介导的反应和免疫系统的其他部分。骨髓衍生的 DC 遗传小鼠模型以及人类 DC，将用于研究 DC 如何通过配体进行调节通过 TLR/NFkB 诱导 AhR 和炎症信号的激活。 AhR/Rel 的全基因组鉴定将进行结合位点和与基因表达相关的分析。结合位点的突变体将是生成以验证是否确实需要特定的结合事件来调节目标的表达基因。蛋白质-蛋白质相互作用研究将确定 AhR 和 Rel 蛋白质的特定相互作用域并深入了解这些相互作用如何影响每种蛋白质的功能活性以及结果 AhR/NFkB 串扰。一种通过正电子发射无创监测免疫反应的新型体内方法断层扫描（免疫 PET）成像将用于最终显示 AhR 配体如何修改 TLR 介导的 DC、中性粒细胞、B 细胞和 T 细胞在体内的募集和积累。这项研究可以提供明确的暴露于 AhR 激活化合物与炎症发展之间的联系和机制慢性疾病。研究结果将允许更明确定义的终点来评估 AhR 的效果和毒性激活配体，包括环境污染物。这项研究也将为未来提供新的概念 AhR 和 AhRR 作为分子靶标的创新用途，用于炎症、感染、和慢性疾病。