{"doi":"10.1101/2024.06.05.597633","title":"Beta-adrenergic signaling and T-lymphocyte-produced catecholamines are necessary for interleukin 17A synthesis","abstract":"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 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. Methods: Using 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. 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. 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. Conclusions: Our 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486196,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":484312,"name":"Safwan Elkhatib","orcid":"0000-0003-3946-8658","position":1,"is_corresponding":false},{"id":1221472,"name":"Tamara Natour","orcid":"0009-0005-1084-464X","position":2,"is_corresponding":false},{"id":922816,"name":"Emily C. Reed","orcid":"0000-0001-6487-5111","position":3,"is_corresponding":false},{"id":1233797,"name":"Caroline N Jojo","orcid":null,"position":4,"is_corresponding":false},{"id":314765,"name":"Adam J. Case","orcid":"0000-0003-3404-1428","position":5,"is_corresponding":false},{"id":493948,"name":"Tatlock Lauten","orcid":"0000-0002-9325-7213","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T02:07:57.049469Z","pmid":"38895227","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}