The β2-adrenergic receptor agonist terbutaline upregulates T helper-17 cells in a protein kinase A-dependent manner

Gonczi, Catalina M. Carvajal; Hajiaghayi, Mehri; Gholizadeh, Fatemeh; Soares, Marina O.; Touma, Fadi; Naranjo, Carolina; Ríos, Antonio Limay; Pozzebon, Chelsea; Daigneault, T.; Burchell-Reyes, Kelly; Darlington, Peter J.

doi:10.1016/j.humimm.2023.06.007

Cited by 7 publications

(1 citation statement)

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“…During our studies described herein, we struggled to identify any literature that had investigated links between β adrenergic receptors and IL-17A. However, one group has recently published a series of papers demonstrating the β2-agonist, terbutaline, could promote T H 17 polarization in CD4 + T-lymphocytes from human peripheral blood mononuclear cells ( Carvajal Gonczi et al, 2023 ; Carvajal Gonczi et al, 2017 ). These findings agree with our data presented here suggesting β receptors are necessary for complete IL-17A production.…”

Section: Discussionmentioning

confidence: 99%

Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis

Lauten,

Elkhatib,

Natour

et al. 2024

Preprint

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BackgroundPost-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a preclinical model of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear.MethodsUsing a modified version of repeated social defeat stress (RSDS) that allows for both males and females, we assessed the impact of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte IL-17A generation. Additionally, we explored the impact of adrenergic signaling and T-lymphocyte-produced catecholamines on both CD4+ and CD8+ T-lymphocytes polarized to IL-17A-producing phenotypes ex vivo.ResultsOnly pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Furthermore, ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Indeed, pharmacological depletion of catecholamines both in vivo and ex vivo abrogated T-lymphocyte IL-17A production demonstrating the importance of immune-generated neurotransmission in pro-inflammatory cytokine generation.ConclusionsOur data depict a novel role for β1/2 adrenergic receptors and autologous catecholamine signaling during T-lymphocyte IL-17A production. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.

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Section: Discussionmentioning

confidence: 99%

Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis

Lauten,

Elkhatib,

Natour

et al. 2024

Preprint

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TH17/Treg lymphocyte balance is regulated by beta adrenergic and cAMP signaling

Lauten,

Elkhatib,

Natour

et al. 2025

Brain, Behavior, and Immunity

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β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner

Hajiaghayi,

Gholizadeh,

Han

et al. 2024

Preprint

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IntroductionAdrenergic receptors regulate metabolic, cardiovascular and immunological functions in response to the sympathetic nervous system. The effect of β2-adrenergic receptor (AR) as a high-expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional β2-AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4+ T (Th1, Th2, Th17) cells and polarized naïve Th17 cells highlighting its potential for IL-17A suppression via a non-canonical β2AR cell-signaling pathway.MethodsThe effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naïve Th17 cells activated with antiCD3/antiCD28/antiCD2 ImmunoCult reagent. IFN-γ, IL-4, and IL-17A which are primarily derived from Th1, Th2, and Th17 cells respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR/Cas9. Protein expression of phosphorylated-serine133-CREB and phosphorylated-NF-κB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry.ResultsNebivolol treatment decreased IL-17A and IFN-γ secretion by activated-memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A+ Th cells and downregulated RORC expression. Unlike the β2-AR agonist terbutaline, nebivolol inhibited the shift of naïve CD4+ T cells towards the Th17 phenotype. IL-10 and proliferation index remained unchanged. Nebivolol-treated β2-knockout memory Th cells showed significant inhibition of β2AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-κB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control.ConclusionsThe findings demonstrate that nebivolol acts through a β2-AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing phosphorylation of NF-κB. This highlights nebivolol’s potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.

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The β2-adrenergic receptor agonist terbutaline upregulates T helper-17 cells in a protein kinase A-dependent manner

Cited by 7 publications

References 47 publications

Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis

Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis

TH17/Treg lymphocyte balance is regulated by beta adrenergic and cAMP signaling

β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner

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