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

Autor: Lauten TH; Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States., Elkhatib SK; Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA, United States., Natour T; Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States., Reed EC; Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States., Jojo CN; Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States., Case AJ; Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States. Electronic address: acase@tamu.edu.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2025 Jan; Vol. 123, pp. 1061-1070. Date of Electronic Publication: 2024 Nov 13.
DOI: 10.1016/j.bbi.2024.11.013
Abstrakt: Background: 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.
Methods: 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 H 17).
Results: 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.
Conclusions: Our data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of T H 17/Treg lymphocytes. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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