T H 17/Treg lymphocyte balance is regulated by beta adrenergic and cAMP signaling

• Published in: Brain, behavior, and immunity behavior, and immunity, 2025-01, Vol.123, p.1061
• Main Authors: Lauten, Tatlock H, Elkhatib, Safwan K, Natour, Tamara, Reed, Emily C, Jojo, Caroline N, Case, Adam J
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacology; Animals; Cell Differentiation; Cyclic AMP - metabolism; Disease Models, Animal; Female; Interleukin-17 - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Adrenergic, beta - metabolism; Receptors, Adrenergic, beta-1 - metabolism; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction; Social Defeat; Stress, Psychological - immunology; Stress, Psychological - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism
• ISSN: 1090-2139
• DOI: 10.1016/j.bbi.2024.11.013

Post-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 mouse model of repeated social defeat stress (RSDS) that recapitulates certain features 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. Using a modified version of RSDS that allows for both males and females, as well as ex vivo models of T-lymphocyte polarization, we assessed the impact and mechanism of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte differentiation to IL-17A-producing subtypes (i.e., T 17). Only 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. 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. Furthermore, cyclic AMP (cAMP) was demonstrated to be mechanistically involved in driving IL-17A production in T-lymphocytes, and amplifying cAMP signaling could restore IL-17A deficits caused by the absence of β1/2 signaling. Last, removal of β1/2 and cAMP signaling, even in IL-17A polarizing conditions, promoted regulatory T-lymphocyte (Treg) polarization, suggesting adrenergic signaling plays a role in the switching between pro- and anti-inflammatory T-lymphocyte subtypes. Our data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of T 17/Treg lymphocytes. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.