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

Abstract

Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that β2-adrenergic receptor (β2AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL-12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although β2AR stimulation in DC induces protein kinase A–dependent cAMP-responsive element–binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A–independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratio following β2AR stimulation, LPS-stimulated DC promoted the generation of CD4+ T cells that, upon TCR engagement, produced lower amounts of IFN-γ and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which β2AR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function.

Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma

“…Tumor immunosuppressive microenvironment inhibits dendritic cell functions [64, 65]. Especially, norepinephrine released in the microenvironment alters antigen presentation by dendritic cells, which reduces cytotoxic T-cell priming [66, 67]. Here we observed that propranolol decreases the number of dendritic cells in the primary tumor and improves CD8 + T-cell activity.…”

β2 Adrenoceptors are underexpressed in peripheral blood mononuclear cells and associated with a better metabolic profile in central obesity

“…β 2 ARs are the most expressed AR on immune cells and considered the main mediators of CA immune effects; their activation usually results in anti-inflammatory effects 6 , 20 , 21 . Indeed, stimulation of β 2 AR modulates cytokine production by activated innate immune cells, primarily inhibiting proinflammatory cytokines, such as TNF-α, IL-12 and IL-6, and by increasing IL-10 and IL-33 release by these cells 22 - 24 .…”

β-Adrenoceptors Trigger Melatonin Synthesis in Phagocytes

“…Regarding the dendritic cells, it is well-known that these specialized phagocytes are responsible for bridging innate and adaptive immune responses [49], and that β-stimulation turns DCs to an anti-inflammatory state [50] and triggers T cell differentiation [51]. Indeed, sympathetic stimulation is essential for triggering the recovery phase of an immune response [52,53] in lymph nodes [54], bone marrow cells [55], and gut macrophages [56].…”