Abstract
Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the β2-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4+ T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or β2-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4+ T cells in both groups. Blockade of the β2-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the β2-adrenoreceptor agonist formoterol did not influence norepinephrine’s inhibitory effect on cytokine production in both groups. The blockade of the β2-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, β2-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4+ T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4+ T cells in MS could be mediated via β2-adrenoreceptor activation.
Highlights
Multiple sclerosis (MS) is the most common demyelinating and neurodegenerative disease of the central nervous system (CNS), which predominantly affects young adults.The study of neuroimmune interaction is one of the most rapidly developing areas in MS research
We found that norepinephrine suppressed IL-17 and IFN-γ production by stimulated peripheral blood mononuclear cells (PBMCs) in both groups (Figure 1c,d), which is similar to the influence of norepinephrine on CD4+ T cells
Th17 cells are considered to be a crucial factor of neuroinflammation in MS
Summary
Multiple sclerosis (MS) is the most common demyelinating and neurodegenerative disease of the central nervous system (CNS), which predominantly affects young adults.The study of neuroimmune interaction is one of the most rapidly developing areas in MS research. Biogenic amines’ involvement in MS pathogenesis is confirmed by the influence of serotoninergic and dopaminergic drugs on experimental encephalomyelitis (EAE) and MS course and the impact of diseasemodifying therapeutics (DMT) of MS on the production of catecholamines by the immune cells [2,3,4]. In line with these data, the repurposing of dopaminergic, noradrenergic, and serotoninergic therapeutics as additional pathogenetic treatments in MS is discussed [3,4]
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