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.

项目概要 神经递质和激素是神经系统和免疫系统之间的纽带。他们之中， 去甲肾上腺素和肾上腺素在交感神经节后神经元中合成 系统和肾上腺髓质。释放后，它们与表达于 免疫细胞。值得注意的是，β2AR异常表达和基因多态性与多种类型相关 自身免疫性疾病。然而，β2AR 信号传导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，我们之前对小鼠模型的研究发现 β2AR 在免疫发育和重建中未被认识到的主要二分作用：1）在特定条件下 在无病原体 (SPF) 条件下，β2AR 缺乏会导致胸腺 T 细胞发育显着减少 与骨髓 (BM) 中 CD115+ 骨髓细胞发育增加形成对比； 2) 胸腺和髓细胞 发育表型在同种异体后的免疫重建过程中明显更加明显 造血细胞移植（allo-HCT）； 3) β2AR在成熟外周T细胞中发挥不同作用 导致移植物抗宿主病（GVHD）结果不同的细胞亚群和骨髓细胞亚群。一起， 这些发现强调了 β2AR 信号传导在维持免疫稳态中的关键和基本作用 和调节免疫反应。因此，本研究将追求三个具体目标来测试总体 假设 β2AR 信号传导通过与 规范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 信号传导调节 T 细胞发育、重建和 GVHD 的机制。目标 2 将定义 β2AR 信号传导调节 CD115+ 骨髓细胞发育、重建和 GVHD 的机制。 目标 3 将研究 β2AR 药理干预的转化潜力和机制。我们将使用 无偏见的 RNA-seq 转录组学方法以及流式细胞术、CyTOF 质谱流式细胞术和 Seahorse 代谢测定结合细胞类型特异性 β2AR 敲除 (Cre-LoxP) 来定义分子机制 用于 T 细胞和骨髓细胞的分化和功能。在allo-HCT的背景下，我们还将研究其影响 这些机制对GVHD和GVT效应的影响。这个项目不仅可以加深我们对 中枢和外周适应性和先天免疫细胞中 β2AR 信号传导的基本机制 免疫器官，但它也可以解释 β2AR 信号传导如何导致免疫疾病和同种异体 HCT 基于免疫疗法。因此，这项研究可能对基于治疗原理的重要影响 β2AR 信号传导的操纵。由于 β2AR 激动剂和拮抗剂已经广泛使用，新的 这项研究产生的临床试验可以在接受 allo-HCT 治疗的患者中快速实施 治疗血癌或其他血液或免疫疾病，allo-HCT 可以治愈这些疾病。