{"doi":"10.1172/jci187063","title":"Activin A activation of Smad3 mitigates innate inflammation in mouse models of psoriasis and sepsis","abstract":"Phosphorylation of Smad3 is a critical mediator of TGF-β signaling, which plays an important role in regulating innate immune responses. However, whether Smad3 activation can be regulated in innate immune cells in TGF-β-independent contexts remains poorly understood. Here, we show that Smad3 is activated through the phosphorylation of its C-terminal residues (pSmad3C) in murine and human macrophages in response to bacterial and viral ligands, and this activation is mediated by activin A in a TGF-β-independent manner. Specifically, infectious ligands, such as LPS, induced secretion of activin A through the transcription factor STAT5 in macrophages, and activin A signaling in turn activated pSmad3C. This activin A/Smad3 axis controlled mitochondrial ATP production and ATP conversion into adenosine by CD73 in macrophages, enforcing an antiinflammatory mechanism. Consequently, mice with a deletion of activin A receptor 1b specifically in macrophages (Acvr1bfl/fl-Lyz2cre) succumbed more to sepsis as a result of uncontrolled inflammation and exhibited exacerbated skin disease in a mouse model of imiquimod-induced psoriasis. Thus, we have revealed a previously unrecognized natural brake to inflammation in macrophages that occurs through the activation of Smad3 in an activin A-dependent manner.","journal":"Journal of Clinical Investigation","year":2025,"id":516531,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"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":900358,"name":"Yun-Ji Lim","orcid":null,"position":1,"is_corresponding":false},{"id":277457,"name":"Wenwen Jin","orcid":"0000-0001-7771-3058","position":2,"is_corresponding":false},{"id":277454,"name":"Na Liu","orcid":"0000-0001-9903-1314","position":3,"is_corresponding":false},{"id":70621,"name":"Liliana Catherine Patiño","orcid":"0000-0002-1710-9809","position":4,"is_corresponding":false},{"id":230854,"name":"Weiwei Chen","orcid":"0000-0001-7681-3962","position":5,"is_corresponding":false},{"id":363360,"name":"James Warren","orcid":"0000-0002-6290-2785","position":6,"is_corresponding":false},{"id":302989,"name":"Daniel Martı́n","orcid":"0000-0002-8880-9087","position":7,"is_corresponding":false},{"id":70680,"name":"Robert J. Morell","orcid":"0000-0003-1537-7356","position":8,"is_corresponding":false},{"id":363363,"name":"Gabriela Dveksler","orcid":"0000-0003-3037-1155","position":9,"is_corresponding":false},{"id":218579,"name":"Grace L. Su","orcid":"0000-0002-8701-774X","position":10,"is_corresponding":false},{"id":497251,"name":"Wanjun Chen","orcid":"0000-0002-8398-4548","position":11,"is_corresponding":false},{"id":1021229,"name":"Thierry Gauthier","orcid":"0009-0004-3417-2481","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"40067393","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":[]}