Beta-2 adrenergic signaling in immune homeostasis and reconstitution

免疫稳态和重建中的 Beta-2 肾上腺素能信号传导

• 批准号: 10610471
• 负责人: Xuefang Cao
• 金额: $ 76.6万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610471
• 关键词: Adrenal Medulla; Adrenergic Agents; Adrenergic Agonists; Allogenic; Autoimmune Diseases; Biological Assay; Bone Marrow; Bone Marrow Cells; CSF1R gene; Cell Count; Cell Differentiation process; Cell physiology; Cells; Clinical Trials; Collaborations; Complex; Cre-LoxP; Cytometry; Dendritic Cells; Development; Disease; Epinephrine; Flow Cytometry; Functional disorder; Genes; Genetic Polymorphism; Genus Hippocampus; Hematological Disease; Hematopoietic Neoplasms; Homeostasis; Hormones; Host Defense; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immune system; Immunotherapy; Intervention; Knock-out; Ligands; Link; Macrophage; Macrophage Colony-Stimulating Factor; Mature T-Lymphocyte; Metabolic; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Nervous System; Neuroimmune; Neurons; Neurotransmitters; Norepinephrine; Organ; Outcome; Pathogenesis; Patients; Peripheral; Phenotype; Play; Proliferating; Publishing; Receptor Signaling; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Sympathetic Nervous System; System; T cell differentiation; T cell reconstitution; T cell response; T-Cell Depletion; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Thymus Gland; Transplantation; adaptive immunity; antagonist; beta-2 Adrenergic Receptors; blood treatment; cell type; germ free condition; graft vs host disease; hematopoietic cell transplantation; immune reconstitution; improved; metabolic fitness; migration; monocyte; mouse model; myeloid cell development; peripheral lymphoid organ; pharmacologic; reconstitution; restraint; transcriptome sequencing; transcriptomics; translational potential

Project Summary Neurotransmitters and hormones serve as a link between the nervous and immune systems. Among them, norepinephrine and epinephrine are synthesized in the postganglionic neurons of the sympathetic nervous system and the adrenal medulla. Upon release, they engage the β2-adrenergic receptor (β2AR) expressed on immune cells. Notably, β2AR abnormal expression and gene polymorphisms are associated with several types of autoimmune diseases. However, mechanisms by which β2AR signaling dysfunction contribute to these diseases remain largely unknown. In this context, our studies with mouse models have uncovered previously unappreciated major dichotomous roles of β2AR in immune development and reconstitution: 1) Under specific pathogen free (SPF) condition, β2AR deficiency causes significantly reduced T cell development in thymus in contrast to increased CD115+ myeloid cell development in bone marrow (BM); 2) Both thymic and myeloid development phenotypes are remarkably more manifested during immune reconstitution following allogeneic hematopoietic cell transplantation (allo-HCT); 3) β2AR plays differential roles in in mature peripheral T cell subsets and myeloid cell subsets that result in different outcome in graft-versus-host disease (GVHD). Together, these findings highlight the critical and fundamental role of β2AR signaling in maintaining immune homeostasis and regulating immune response. Therefore, this study will pursue three specific aims to test an overarching hypothesis that β2AR signaling regulates immune development and reconstitution via cross-talking with canonical immune signaling pathways and/or fine-tuning metabolic fitness of immune cells. Aim 1 will determine mechanisms by which β2AR signaling regulates T cell development, reconstitution and GVHD. Aim 2 will define mechanisms by which β2AR signaling regulates CD115+ myeloid cell development, reconstitution and GVHD. Aim 3 will study the translational potential and mechanisms of pharmacologic β2AR intervention. We will use unbiased RNA-seq transcriptomic approach along with flow cytometry, CyTOF mass cytometry and Seahorse metabolic assay combined with cell type-specific β2AR knockout (Cre-LoxP) to define the molecular mechanisms for T cell and myeloid cell differentiation and function. In the setting of allo-HCT, we will also examine the impact of these mechanisms on GVHD and GVT effect. This project will not only improve our understanding of the fundamental mechanisms of β2AR signaling in adaptive and innate immune cells in central and peripheral immune organs, but it may also explain how β2AR signaling contributes to immunologic disorders and allo-HCT based immunotherapy. Therefore, this study may have important ramifications on therapeutic rationale based upon manipulation of β2AR signaling. Since β2AR agonists and antagonists are already widely available, new clinical trials emanating from this research could be rapidly implemented for patients receiving allo-HCT for treatment of blood cancers, or other hematologic or immunologic diseases in which allo-HCT can be curative.

项目摘要 神经递质和激素是神经系统和免疫系统之间的联系。其中， 去甲肾上腺素和肾上腺素在交感神经的节后神经元中合成 系统和肾上腺髓质。释放后，它们与表达在细胞表面的β2-肾上腺素能受体（β2AR）结合， 免疫细胞值得注意的是，β 2 AR异常表达和基因多态性与几种类型的乳腺癌相关， 自身免疫性疾病然而，β2AR信号功能障碍导致这些的机制， 疾病在很大程度上仍然未知。在这种情况下，我们对小鼠模型的研究已经揭示了以前 β 2 AR在免疫发育和重建中的主要作用：1）在特异性 无病原体（SPF）条件下，β 2 AR缺乏导致胸腺中T细胞发育显著减少， 与骨髓（BM）中增加的CD 115+髓样细胞发育相反; 2）胸腺和髓样细胞两者 发育表型在同种异体移植后的免疫重建过程中明显更多地表现出来。 3）β 2 AR在外周血成熟T细胞中发挥不同的作用 亚群和骨髓细胞亚群，导致移植物抗宿主病（GVHD）的不同结果。在一起， 这些发现强调了β2AR信号在维持免疫稳态中的关键和基础作用 和调节免疫反应。因此，本研究将追求三个具体目标，以测试一个总体的 假设β2AR信号通过与β 2AR信号的交互作用调节免疫发育和重建， 典型的免疫信号传导途径和/或微调免疫细胞的代谢适应性。目标1将决定 β2AR信号调节T细胞发育、重建和GVHD的机制。目标2将定义 β2AR信号调节CD 115+髓系细胞发育、重建和GVHD的机制。 目的3研究β 2 AR的翻译潜能及药物干预的机制。我们将使用 无偏RNA-seq转录组学方法沿着流式细胞术、CyTOF质谱细胞术和Seahorse 代谢试验结合细胞类型特异性β2AR敲除（Cre-LoxP）来确定分子机制 用于T细胞和骨髓细胞的分化和功能。在allo-HCT的背景下，我们还将研究 这些机制对GVHD和GVT的影响。这个项目不仅能增进我们对 中枢和外周适应性和先天性免疫细胞中β 2 AR信号传导的基本机制 但它也可能解释β2AR信号如何有助于免疫疾病和allo-HCT 基于免疫疗法。因此，这项研究可能会对治疗原理产生重要影响， β2AR信号的调控。由于β2AR激动剂和拮抗剂已经广泛使用， 这项研究产生的临床试验可以迅速实施，用于接受allo-HCT的患者， 治疗血癌或其中allo-HCT可以治愈的其它血液学或免疫学疾病。