Sympathetic Neuronal Activation Triggers Myeloid Progenitor Proliferation and Differentiation

Abstract

There is a growing body of research on the neural control of immunity and inflammation. However, it is not known whether the nervous system can regulate the production of inflammatory myeloid cells from hematopoietic progenitor cells in disease conditions. Myeloid cell numbers in diabetic patients were strongly correlated with plasma concentrations of norepinephrine, suggesting the role of sympathetic neuronal activation in myeloid cell production. The spleens of diabetic patients and mice contained higher numbers of tyrosine hydroxylase (TH)-expressing leukocytes that produced catecholamines. Granulocyte macrophage progenitors (GMPs) expressed the β adrenergic receptor, a target of catecholamines. Ablation of splenic sympathetic neuronal signaling using surgical, chemical, and genetic approaches diminished GMP proliferation and myeloid cell development. Finally, mice lacking TH-producing leukocytes had reduced GMP proliferation, resulting in diminished myelopoiesis. Taken together, our study demonstrates that catecholamines produced by leukocytes and sympathetic nerve termini promote GMP proliferation and myeloid cell development.

β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells

“…A recent report by McKim et al (45) has shown that psychological stress (exposure to an aggressor mouse) increases hematopoietic stem progenitor cell (HSPC) trafficking from bone marrow to spleen, and promotes differentiation into several types of immunosuppressive cells, including MDSCs. Another report has shown that NE increases proliferation of granulocyte-monocyte progenitors (GMPs) in the spleen and that severing splenic SNS nerves diminishes GMP proliferation and MDSC development (18).…”

“…Nerve fibers present in and around most tissues and organs, as well as tumors (13,16,17), release neurotransmitters and other neuropeptides locally and systemically. The release of catecholamines (norepinephrine [NE] and epinephrine) by ubiquitously distributed sympathetic nerves, and by some special cells such as tyrosine hydroxylase-positive cells in the spleen, can directly stimulate cells bearing adrenergic receptors (ARs) (18). ARs belong to the guanine nucleotide-binding G protein-coupled receptor (GPCR) superfamily (19).…”

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…The NPY of the immune system is mainly derived from the sympathetic nervous system, parenchymal, and immune cells ( Table 1 ). The sympathetic nerve releases NPY to act on the immune organs it innervates ( 15 , 31 , 32 ). Furthermore, splenic tissue sections release NE and NPY spontaneously or under electric field stimulation; subsequently, NPY acts on the Y1R to inhibit the release of interleukin-6 (IL-6) ( 31 ), suggesting that neuronal release of NPY modifies the immune response.…”

An in vivo brain–bacteria interface: the developing brain as a key regulator of innate immunity

“…2,[16][17][18][19] These studies reveal the adult brain as a regulator of adaptive immune response. 20,21 The immune system has been proposed as a 'seventh sense', 22 receiving information from pathogen agents to inform the central nervous system. Studies using invertebrate models suggest that neural circuits receive and integrate stimuli coming from pathogens, via G protein-coupled receptors (GPCRs), to guide the immune response.…”