The Sympathetic Nervous System Mitigates CNS Autoimmunity via β2-Adrenergic Receptor Signaling in Immune Cells

Noradrenaline (NE), the main neurotransmitter released by sympathetic nerve terminals, is known to modulate the immune response. However, the role of the sympathetic nervous system (SNS) on the development of autoimmune diseases is still unclear. Here, we report that the SNS limits the generation of pathogenic T cells and disease development in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). β2-Adrenergic receptor (Adrb2) signaling limits T cell autoimmunity in EAE through a mechanism mediated by the suppression of IL-2, IFN-γ, and GM-CSF production via inducible cAMP early repressor (ICER). Accordingly, the lack of Adrb2 signaling in immune cells is sufficient to abrogate the suppressive effects of SNS activity, resulting in increased pathogenic T cell responses and EAE development. Collectively, these results uncover a suppressive role for the SNS in CNS autoimmunity while they identify potential targets for therapeutic intervention. [Display omitted] •Sympathetic nervous system (SNS) limits CNS autoimmune inflammation•Adrb2 signaling in immune cells mediates the SNS effects on EAE development•Adrb2-mediated SNS suppressive effects involve ICER-driven inhibition of CD4+ T cells Araujo et al. show that neurotransmitters released by the sympathetic nervous system regulate the generation of adaptive immune responses mitigating autoimmune inflammation within the CNS.