Role of adrenergic receptor signalling in neuroimmune communication

Abstract

Neuroimmune communication plays a crucial role in maintaining homeostasis and promptly responding to any foreign insults. Sympathetic nerve fibres are innervated into all the lymphoid organs (bone marrow, thymus, spleen, and lymph nodes) and provide a communication link between the central nervous system (CNS) and ongoing immune response in the tissue microenvironment. Neurotransmitters such as catecholamines (epinephrine and norepinephrine) bind to adrenergic receptors present on most immune and non-immune cells, establish a local neuroimmune-communication system, and help regulate the ongoing immune response. The activation of these receptors varies with the type of receptor-activated, target cell, the activation status of the cells, and timing of activation. Activating adrenergic receptors, specifically β-adrenergic signalling in immune cells leads to activation of the cAMP-PKA pathway or other non-canonical pathways. It predominantly leads to immune suppression such as inhibition of IL-2 secretion and a decrease in macrophages phagocytosis. This review discusses the expression of different adrenergic receptors in various immune cells, signalling, and how it modulates immune cell function and contributes to health and diseases. Understanding the neuroimmune communication through adrenergic receptor signalling in immune cells could help to design better strategies to control inflammation and autoimmunity.

Keywords: AC, Adenylate cyclase; Adrenaline; Adrenergic receptors; CNS, Central Nervous System; DCs, Dendritic cells; Epinephrine; GRK, G protein-coupled receptor kinase; L-DOPA, L-dihydroxyphenylalanine; LPS, Lipopolysaccharide; Nerve-driven immunity; Neuroimmune communication; Neurotransmitters; Norepinephrine; PDE, Phosphodiesterase; PKA, Protein kinase A; SNS, Sympathetic nervous system; TNF, Tumor necrosis factor; cAMP, Cyclic adenosine monophosphate.

Graphical abstract

Fig. 1

Synthesis of catecholamines (dopamine, norepinephrine, and epinephrine). The various steps, enzymes and co-factors required for the synthesis are depicted.

Fig. 2

Canonical β2 adrenergic receptor signalling. Binding of norepinephrine secreted by the sympathetic nerve stimulate the β-adrenergic receptor. Due to conformation change by replacement of GDP with GTP, α_s, and βγ subunits of G protein separates from each other, and then α_s activates the enzyme adenylate cyclase, which converts ATP to cAMP, which further phosphorylates GRK2; which in turn activates protein kinase A (PKA). Activated PKA then activation of ERK1/2, MAPK pathway leading to transcription regulation of several important genes.

Fig. 3

Canonical pathways induced by adrenergic receptor signalling. The higher ligand concentration leads to phosphorylation of adrenergic receptors by GRK2. Phosphorylated adrenergic receptors bind to β-arrestin 1. This drives the receptor internalization and which either may get dephosphorylated and recycled back the adrenergic receptor at the plasma membrane or degraded in the lysosome.

Fig. 4

Non-canonical pathways induced by adrenergic receptor signalling. GRK5/6 phosphorylates the adrenergic receptor and then recruits β-arrestin 2. This leads to receptor internalization and generation of second signalling by activating ERK1/2, MAPK, which leads to activation of transcription factors and regulation of gene transcription.