{"doi":"10.1093/immhor/vlaf032","title":"IL-4 and TGF-β regulate inflammatory cytokines and cellular infiltration in the lung and systemic IL-6 in mouse-adapted SARS-CoV-2 infection","abstract":"The pathology of severe COVID-19 is due to a hyperinflammatory immune response persisting after viral clearance. To understand how the immune response to SARS-CoV-2 is regulated to avoid severe COVID-19, we tested relevant immunoregulatory cytokines. Transforming growth factor β (TGF-β), interleukin (IL)-10, and IL-4 were neutralized upon infection with mouse-adapted SARS-CoV-2 (CMA3p20), a model of mild disease; lung inflammation was quantified by histology and flow cytometry at early and late time points. Mild weight loss and lung inflammation including consolidation and alveolar thickening were evident 3 d postinfection (dpi), and inflammation persisted to 7 dpi. Coinciding with early monocytic infiltrates, CCL2 and granulocyte colony-stimulating factor were transiently produced 3 dpi, while IL-12 and CCL5 persisted to 7 dpi, modeling viral and inflammatory phases of disease. Neutralization of TGF-β, but not IL-10 or IL-4, significantly increased lung inflammatory monocytes and elevated serum but not lung IL-6. Neutralization of IL-4 prolonged weight loss and increased early perivascular infiltration without changing viral titer. Anti-IL-4 reduced expression of Arg1, a gene associated with alternative activation of macrophages. Neutralizing TGF-β and IL-4 had differential effects on pathology after virus control. Lung perivascular infiltration was reduced 7 dpi by neutralization of IL-4 or TGF-β, and periairway inflammation was affected by anti-TGF-β, while alveolar infiltrates were not affected by either. Anti-IL-4 prolonged IL-12 to 7 dpi along with reduced IL-10 in lungs. Overall, the immunoregulatory cytokines TGF-β and IL-4 dampen initial inflammation in this mouse-adapted SARS-CoV-2 infection, suggesting that promotion of immunoregulation could help patients in early stages of disease.","journal":"ImmunoHorizons","year":2025,"id":553988,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"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":1228351,"name":"Lucinda Puebla-Clark","orcid":"0000-0002-5363-3026","position":1,"is_corresponding":false},{"id":850037,"name":"María González-Orozco","orcid":"0000-0001-7299-3361","position":2,"is_corresponding":false},{"id":1105616,"name":"Mark Joseph Endrino","orcid":null,"position":3,"is_corresponding":false},{"id":453508,"name":"Thomas R. Shelite","orcid":"0000-0001-6686-6032","position":4,"is_corresponding":false},{"id":244929,"name":"Tseng Hsiang-Chi","orcid":"0000-0001-7745-413X","position":5,"is_corresponding":false},{"id":279912,"name":"Yazmin B. Martinez-Martinez","orcid":null,"position":6,"is_corresponding":false},{"id":502738,"name":"Matthew B. Huante","orcid":"0000-0002-6604-9603","position":7,"is_corresponding":false},{"id":396100,"name":"Hannah G. Federman","orcid":null,"position":8,"is_corresponding":false},{"id":1081769,"name":"Komi Gbédandé","orcid":"0000-0002-3229-5566","position":9,"is_corresponding":false},{"id":105316,"name":"Vineet D. Menachery","orcid":"0000-0001-8803-7606","position":10,"is_corresponding":false},{"id":300714,"name":"Mark C. Siracusa","orcid":"0000-0003-3499-5408","position":11,"is_corresponding":false},{"id":502742,"name":"Mark Endsley","orcid":"0000-0002-5338-1332","position":12,"is_corresponding":false},{"id":107277,"name":"Sara M. 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