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

• 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
• 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

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.

项目总结/摘要 芳烃受体（AhR）在调节免疫应答和暴露于 AhR激活化合物，包括环境毒物，如二恶英，可能有助于 细胞因子的失调和免疫系统疾病的发展。配体依赖性激活 AhR可促进炎性T辅助性Th 17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。在我们对AhR如何调节 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，这是至关重要的理解生理和病理生理免疫 通过AhR介导的反应。这项建议的总体目标是确定人权专员的职能作用， 其特异性阻遏物（AhRR）与Toll样受体（TLR）和NF κ B信号转导相互作用控制功能 以及DC的分化和T细胞活化。AhR对TLR和NFkB信号传导的失调 配体可能是触发免疫系统紊乱的关键步骤。AhR的转录抑制因子， AhRR在AhR途径中实施，尽管在TLR水平仍有许多有待阐明， NFkB信号传导。在过度表达AhRR的转基因小鼠中，我们发现AhRR与以下因素密切相关： 二恶英诱导的炎症基因表达以及LPS介导的炎症反应的调节 LPS休克。因此，AhRR Tg小鼠给了我们机会来认识AhRR是如何参与细胞凋亡的。 调节TLR介导的反应和免疫系统的其他部分。骨髓来源的DC 遗传小鼠模型以及人类DC，将用于研究DC是如何通过配体调节的， 通过TLR/NFkB诱导AhR和炎症信号的激活。AhR/Rel的全基因组鉴定 将进行结合位点和相关基因表达分析。结合位点的突变体将是 生成以验证是否实际需要特定的结合事件来调节靶点的表达 基因.蛋白质相互作用研究将确定AhR和Rel蛋白的特异性相互作用结构域 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 AhR/NFkB串扰。一种通过正电子发射无创监测免疫应答的体内新方法 断层扫描（免疫PET）成像将用于最终显示AhR配体如何修饰TLR介导的 DC、嗜中性粒细胞、B细胞和T细胞在体内的募集和积累。这项研究可以提供一个明确的 暴露于AhR激活化合物与炎症发展之间的联系和机制 慢性病研究结果将允许更明确定义的终点，以评估AhR的作用和毒性 活化配体，包括环境污染物。本研究也将为今后的研究提供新的思路 AhR和AhRR作为分子靶标在炎症、感染 和慢性疾病。