Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

Abstract

Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells.

Norepinephrine Controls Effector T Cell Differentiation through β2-Adrenergic Receptor–Mediated Inhibition of NF-κB and AP-1 in Dendritic Cells

“…However, we did not find any difference in IL-12 secretion between WT and IL-10 2/2 LPS-DC that had been treated with b 2 AR agonists, suggesting an IL-10-independent mechanism. b 2 AR belong to the G protein-coupled receptor family and are usually associated with the stimulatory subtype of G protein (G s ) (4,33). The canonical b 2 AR signaling pathway activation results in increased adenylyl cyclase activity that leads to augmented intracellular cAMP levels, which, in turn, promote PKA-mediated CREB phosphorylation (4,33).…”

“…b 2 AR belong to the G protein-coupled receptor family and are usually associated with the stimulatory subtype of G protein (G s ) (4,33). The canonical b 2 AR signaling pathway activation results in increased adenylyl cyclase activity that leads to augmented intracellular cAMP levels, which, in turn, promote PKA-mediated CREB phosphorylation (4,33). Indeed, we found that b 2 AR activation in DC also results in increased cAMP levels and PKA-dependent CREB phosphorylation.…”

Cholinergic modulation of the immune system presents new approaches for treating inflammation

“…These noradrenergic neurons provide innervation to all primary and secondary lymphoid tissues, including the bone marrow, spleen and lymph nodes (Jung et al, 2017; Nance and Sanders, 2007). Most immune cells express one or more type of adrenergic receptor (Table 1), but β 2 -adrenoceptors have the widest distribution and mediate most effects of sympathetic nerves on immune function (Bellinger and Lorton, 2014; Elenkov et al, 2000; Lorton and Bellinger, 2015; Padro and Sanders, 2014).…”

“…Most evidence indicates that activation of β 2 -adrenoceptors has immunosuppressive effects on monocytes and macrophages (Lorton and Bellinger, 2015; Padro and Sanders, 2014). However, these effects are context dependent, and pro-inflammatory responses can occur under some circumstances.…”

Acute Traumatic Brain Injury Induces CD4⁺ and CD8⁺ T Cell Functional Impairment by Upregulating the Expression of PD-1 via the Activated Sympathetic Nervous System

“…The sympathetic nervous system (SNS) communicates with all cells of the immune system, regulating their function through the release of norepinephrine (NE), and activating intercellular signaling pathway via the adrenergic receptors (ARs) expressed on immunocytes [13, 14]. Generally, TBI initially triggers an increase of SNS activity and exaggerated NE release, part of the host response to injury which can subsequently influence the immune function [15, 16].…”