{"doi":"10.1016/j.immuni.2022.10.004","title":"The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands","abstract":"Prior exposure to microenvironmental signals could fundamentally change the response of macrophages to subsequent stimuli. It is believed that T helper-2 (Th2)-cell-type cytokine interleukin-4 (IL-4) and Toll-like receptor (TLR) ligand-activated transcriptional programs mutually antagonize each other, and no remarkable convergence has been identified between them. In contrast, here, we show that IL-4-polarized macrophages established a hyperinflammatory gene expression program upon lipopolysaccharide (LPS) exposure. This phenomenon, which we termed extended synergy, was supported by IL-4-directed epigenomic remodeling, LPS-activated NF-κB-p65 cistrome expansion, and increased enhancer activity. The EGR2 transcription factor contributed to the extended synergy in a macrophage-subtype-specific manner. Consequently, the previously alternatively polarized macrophages produced increased amounts of immune-modulatory factors both in vitro and in vivo in a murine Th2 cell-type airway inflammation model upon LPS exposure. Our findings establish that IL-4-induced epigenetic reprogramming is responsible for the development of inflammatory hyperresponsiveness to TLR activation and contributes to lung pathologies.","journal":"Immunity","year":2022,"id":235618,"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":78,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":514947,"name":"László Halász","orcid":"0000-0003-4726-7012","position":1,"is_corresponding":false},{"id":237496,"name":"Bence Dániel","orcid":"0000-0002-2410-8767","position":2,"is_corresponding":false},{"id":855304,"name":"Zsofia Varga","orcid":null,"position":3,"is_corresponding":false},{"id":753785,"name":"Krisztián Bene","orcid":"0000-0002-9963-8172","position":4,"is_corresponding":false},{"id":855305,"name":"Apolka Domokos","orcid":null,"position":5,"is_corresponding":false},{"id":396983,"name":"Marten A. Hoeksema","orcid":"0000-0001-5981-121X","position":6,"is_corresponding":false},{"id":80485,"name":"Zeyang Shen","orcid":"0000-0003-3870-1390","position":7,"is_corresponding":false},{"id":550893,"name":"Wilhelm K. Berger","orcid":"0000-0003-0727-7064","position":8,"is_corresponding":false},{"id":551531,"name":"Tímea Cseh","orcid":null,"position":9,"is_corresponding":false},{"id":855306,"name":"Karoly Jambrovics","orcid":null,"position":10,"is_corresponding":false},{"id":550891,"name":"Zsuzsanna Kolostyák","orcid":"0000-0003-3337-7210","position":11,"is_corresponding":false},{"id":854385,"name":"Ferenc Fenyvesi","orcid":"0000-0003-2890-0783","position":12,"is_corresponding":false},{"id":854386,"name":"Judit Váradi","orcid":"0000-0003-1885-164X","position":13,"is_corresponding":false},{"id":550892,"name":"Szilárd Póliska","orcid":"0000-0002-9722-251X","position":14,"is_corresponding":false},{"id":551530,"name":"György Hajas","orcid":null,"position":15,"is_corresponding":false},{"id":550897,"name":"István Szatmári","orcid":"0000-0001-5260-1498","position":16,"is_corresponding":false},{"id":20022,"name":"Christopher K. Glass","orcid":"0000-0003-4344-3592","position":17,"is_corresponding":false},{"id":126396,"name":"Attila Bácsi","orcid":"0000-0002-2311-2975","position":18,"is_corresponding":false},{"id":483508,"name":"László Nagy","orcid":"0000-0001-6653-2155","position":19,"is_corresponding":false},{"id":73324,"name":"Zsolt Czimmerer","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T00:21:53.333008Z","pmid":"36323312","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":[]}