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Principal Investigator: Xuefang Cao
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2024
Award: $750,705
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Adrenal Medulla><Adrenaline><Adrenergic Agents><Adrenergic Agonists><Adrenergic Drugs><Adrenergic Receptor Agonist><Adrenergics><Adrenomimetics><Allogenic><Assay><Autoimmune Diseases><Autoregulation><Bioassay><Biological Assay><Blood Diseases><Blood monocyte><Bone Marrow><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Marrow Reticuloendothelial System><CD115><CD115 Gene><CSF-1><CSF1R><CSF1R gene><CSFMR><Catecholamine Receptor><Cell Body><Cell Communication and Signaling><Cell Count><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Number><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical Trials><Collaborations><Colony Stimulating Factor 1 Receptor Gene><Colony-Stimulating Factor 1><Complex><Cre-Lox><Cre-LoxP><Cre/LoxP><Cytometry><Dendritic Cells><Development><Disease><Disorder><Dysfunction><Endocrine Gland Secretion><Epinephrine><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Genes><Genetic Polymorphism><Genus Hippocampus><GvHD><HSC transplantation><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Homeostasis><Homologous Wasting Disease><Hormones><Host Defense><Human><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune mediated therapy><Immune response><Immune signaling><Immune system><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically Directed Therapy><Immunotherapy><Innate Immunity><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knock-out><Knockout><Levarterenol><Levonorepinephrine><Ligands><Link><M-CSF><Macrophage><Macrophage Colony-Stimulating Factor><Malignant Hematopoietic Neoplasm><Marrow monocyte><Mature T-Cell><Mature T-Lymphocyte><Metabolic><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><Native Immunity><Natural Immunity><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Nervous System><Neural Cell><Neurocyte><Neuroimmune><Neurologic Body System><Neurologic Organ System><Neurons><Neurotransmitters><Non-Specific Immunity><Nonspecific Immunity><Noradrenaline><Norepinephrine><Organ><Outcome><Pathogenesis><Patients><Peripheral><Phenotype><Physiological Homeostasis><Physiopathology><Play><Proliferating><Publishing><RNA Seq><RNA sequencing><RNAseq><Receptor Signaling><Regulation><Reporting><Research><Role><Runt Disease><Seahorse><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><Sympathetic Nervous System><System><T cell differentiation><T cell reconstitution><T cell response><T-Cell Depletion><T-Cell Development><T-Cell Ontogeny><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Development><T-Lymphocyte Subsets><T-cell depletion therapy><T-lymphocyte depletion therapy><Technology><Testing><Therapeutic><Therapeutic Epinephrine><Therapeutic Hormone><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Transplantation><Veiled Cells><adaptive immunity><adrenal gland medulla><antagonism><antagonist><autoimmune condition><autoimmune disorder><autoimmunity disease><beta-2 Adrenergic Receptors><biological signal transduction><blood cancer><blood disorder><blood treatment><c-FMS><c-fms Genes><c-fms Proto-Oncogenes><cancer of blood><cancer of the blood><cell type><cellular differentiation><developmental><flow cytophotometry><germ free condition><graft versus host disease><graft vs host disease><graft vs. host disease><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor cell transplantation><host response><immune reconstitution><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><improved><interventional strategy><metabolic fitness><migration><monocyte><mouse model><murine model><myeloid cell development><neuronal><pathophysiology><peripheral lymph organ><peripheral lymphoid organ><pharmacologic><polymorphism><reconstitute><reconstitution><restraint><social role><specific pathogen free><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translational opportunities><translational potential><transplant><β-2 Adrenoceptor><β2 Adrenergic Receptor>