{"doi":"10.3389/fimmu.2025.1661114","title":"The ATP-mediated cytokine release by macrophages is down-modulated by unconventional α9* nicotinic acetylcholine receptors","abstract":"Objective: The clinical interest in mechanisms controlling the biosynthesis and release of the pro-inflammatory cytokine interleukin (IL)-1β is outstanding, as IL-1β is associated with life-threatening inflammatory diseases including hyperinflammation caused by extracellular ATP originating from damaged cells. Previously, we identified a cholinergic mechanism controlling ATP-dependent IL-1β release via metabotropic signaling of unconventional nicotinic acetylcholine receptors (nAChRs) containing subunits α7 and α9* (denoting homomeric or heteromeric α9) in monocytes. This study examines whether this mechanism is active in human macrophages (THP-1 cell-derived, peripheral blood mononuclear cell-derived, and peritoneal macrophages). Methods: ) was analyzed using real-time RT-PCR. The efficiency of the differentiation protocols used was assessed by surface markers and metabolic conversion rate analysis. Cholinergic control of ATP-induced IL-1β, IL-18, and IL-1α release was tested using nAChR agonists and conopeptides antagonizing α7 and α9* nAChRs. Results: All nAChR subunits were expressed by all cells analyzed. Activation of nAChRs efficiently inhibited the ATP-mediated IL-1β release by macrophages, while ATP-independent release remained unaffected. Moreover, the nAChR agonists inhibited the release of IL-18 and IL-1α. The inhibitory effect was reversed by subunit-specific conopeptides, indicating the involvement of unconventional nAChRs containing subunits α7 and α9*. Conclusion: We conclude that the cholinergic control of ATP-mediated IL-1β release is active in human monocytes and in macrophages and that nAChR agonists can also regulate the release of IL-18 and IL-1α. This mechanism specifically regulates the ATP-induced cytokine release, without suppressing ATP-independent cytokine release. Thus, unconventional α9* nAChRs are promising therapeutic targets for ATP-induced inflammatory diseases, including sterile hyperinflammation.","journal":"Frontiers in Immunology","year":2025,"id":535180,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1419290,"name":"Dominik Hanke","orcid":null,"position":1,"is_corresponding":false},{"id":896910,"name":"Vijay Kumar Singh","orcid":"0000-0002-4932-3076","position":2,"is_corresponding":false},{"id":905178,"name":"H. 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Michael McIntosh","orcid":"0000-0001-9939-7981","position":12,"is_corresponding":false},{"id":897669,"name":"Juliane Liese","orcid":null,"position":13,"is_corresponding":false},{"id":1418759,"name":"Sybille Mazurek","orcid":"0000-0002-9104-7677","position":14,"is_corresponding":false},{"id":448649,"name":"Veronika Grau","orcid":"0000-0001-7512-2051","position":15,"is_corresponding":false},{"id":448643,"name":"Katrin Richter","orcid":"0000-0002-2450-1083","position":16,"is_corresponding":false},{"id":474956,"name":"Philipp Wolf","orcid":"0000-0001-6779-4325","position":0,"is_corresponding":true}],"reference_count":125,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:51:56.297114Z","pmid":"41221292","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":[]}