{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:37:21Z","timestamp":1790278641068,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Sex differences strongly influence immune responses and susceptibility to inflammatory diseases, yet how biological sex shapes immune regulatory mechanisms in chronic obstructive pulmonary disease (COPD) remains poorly understood. Neutrophils are key drivers of COPD pathogenesis, but whether biological sex shapes their inflammatory programming has not been systematically investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here we integrated transcriptomic and epigenomic profiling of circulating neutrophils from male and female COPD patients to define sex-dependent regulatory programs in innate immune cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Unsupervised analyses revealed that sex represents a major source of transcriptional variation in neutrophils. Although COPD induced a shared disease-associated transcriptional signature in both sexes, the magnitude and functional orientation of this response differed markedly. Male COPD neutrophils displayed robust enrichment of interferon signaling, cytokine-mediated pathways, and inflammatory networks. These transcriptional changes in male were accompanied by widespread H3K27ac enrichment at promoters and enhancers of inflammatory loci, and by elevated plasma levels of CXCL8, TNF-\u03b1, IFN-\u03b1, IFN-\u03b3, and VEGF inflammatory mediators. In contrast, female neutrophils preferentially exhibited transcriptional programs related to autophagy and vesicle-mediated processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings define a model in which COPD elicits a shared neutrophil transcriptional framework that is amplified through sex-specific epigenetic and inflammatory feedback. This male-biased inflammatory reprogramming provides a mechanistic basis for sex differences in COPD immunopathology and highlights the importance of incorporating sex as a biological variable in the development of precision therapies for chronic inflammatory disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1824596","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:10:20Z","timestamp":1779912620000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Sex-dependent transcriptional and epigenetic regulation of neutrophil inflammatory programs in COPD"],"prefix":"10.3389","volume":"17","author":[{"given":"Barbara","family":"Mariotti","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of General Pathology, University of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gasperini","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of General Pathology, University of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Bracaglia","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of General Pathology, University of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Frigenti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of General Pathology, University of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Sartori","sequence":"additional","affiliation":[{"name":"Department of Medicine, Respiratory Medicine Unit, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"di Chiara","sequence":"additional","affiliation":[{"name":"Department of Medicine, Respiratory Medicine Unit, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Sangiovanni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Respiratory Medicine Unit, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Crisafulli","sequence":"additional","affiliation":[{"name":"Department of Medicine, Respiratory Medicine Unit, University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Bazzoni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of General Pathology, University of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccm.2021.06.001","article-title":"Differences between men and women with chronic obstructive pulmonary disease","volume":"42","author":"Jenkins","year":"2021","journal-title":"Clin Chest Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26062747","article-title":"Sex differences in chronic obstructive pulmonary disease: Implications for pathogenesis, diagnosis, and treatment","volume":"26","author":"Czarnota","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-042022-014322","article-title":"Sex, gender, and COPD","volume":"87","author":"Demeo","year":"2025","journal-title":"Annu Rev Physiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1016\/j.celrep.2019.10.019","article-title":"Sex differences in the blood transcriptome identify robust changes in immune cell proportions with aging and influenza infection","volume":"29","author":"Bongen","year":"2019","journal-title":"Cell Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2011.02.001","article-title":"Gender differences in the adipose secretome system in chronic obstructive pulmonary disease (COPD): A pivotal role of leptin","volume":"105","author":"Breyer","year":"2011","journal-title":"Respir Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016021","article-title":"Gender differences in plasma biomarker levels in a cohort of COPD patients: A pilot study","volume":"6","author":"de Torres","year":"2011","journal-title":"PloS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1080\/15412555.2018.1476475","article-title":"Neutrophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease","volume":"15","author":"Butler","year":"2018","journal-title":"COPD J Chronic Obstr Pulm Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00.15110900","article-title":"Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD","volume":"15","author":"Rutgers","year":"2000","journal-title":"Eur Respir J"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2013.05.035","article-title":"Aberrant neutrophil functions in stable chronic obstructive pulmonary disease: The neutrophil as an immunotherapeutic target","volume":"17","author":"Stockley","year":"2013","journal-title":"Int Immunopharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112525","article-title":"Systemic alterations in neutrophils and their precursors in early-stage chronic obstructive pulmonary disease","volume":"42","author":"Kapellos","year":"2023","journal-title":"Cell Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S341623","article-title":"Impact of sex on circulating leukocytes composition in COPD patients","volume":"16","author":"Troianova","year":"2021","journal-title":"Int J COPD"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.04.011","article-title":"Innate immune reprogramming in circulating neutrophils of COPD patients","volume":"156","author":"Mariotti","year":"2025","journal-title":"J Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.03.072","article-title":"Identification of novel differentially methylated sites with potential as clinical predictors of impaired respiratory function and COPD","volume":"43","author":"Bermingham","year":"2019","journal-title":"EBioMedicine"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11010134","article-title":"Systemic and airway epigenetic disruptions are associated with health status in COPD","volume":"11","author":"Hernandez Cordero","year":"2023","journal-title":"Biomedicines"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2003406","DOI":"10.1183\/13993003.03406-2020","article-title":"Epigenetics and pulmonary diseases in the horizon of precision medicine: A review","volume":"57","author":"Benincasa","year":"2021","journal-title":"Eur Respir J"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.05.00034805","article-title":"Standardisation of spirometry","volume":"26","author":"Miller","year":"2005","journal-title":"Eur Respir J"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600138","article-title":"IL-17 promotes neutrophil-mediated immunity by activating microvascular pericytes and not endothelium","volume":"197","author":"Liu","year":"2016","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-631572","article-title":"Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans","volume":"126","author":"Massena","year":"2015","journal-title":"Blood"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13148-021-01126-1","article-title":"The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes","volume":"13","author":"Beacon","year":"2021","journal-title":"Clin Epigenet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2003603117","article-title":"Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism","volume":"117","author":"Gupta","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-024-00671-2","article-title":"Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Beh\u00e7et\u2019s uveitis","volume":"10","author":"Wang","year":"2024","journal-title":"Cell Discov"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1748097","article-title":"Immune modulation by sex hormones: unveiling the complex interplay and regulatory networks","volume":"17","author":"Wan","year":"2026","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/IN9.0000000000000036","article-title":"The emerging role for neutrophil mitochondrial metabolism in lung inflammation","volume":"6","author":"Maldarelli","year":"2024","journal-title":"Immunometabolism (United States)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1698832","article-title":"From metabolic alterations to chronic inflammation: mechanisms and immunoregulation of metabolic reprogramming in COPD","volume":"16","author":"Zeng","year":"2025","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1101\/2025.09.22.677957","article-title":"IFNAR1 + neutrophils orchestrate chronic inflammatory damage through mitochondrial remodeling","author":"Rodrigues","year":"2025","journal-title":"bioRxiv"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20353","article-title":"Cigarette smoke promotes COPD by activating platelet-activating factor receptor and inducing neutrophil autophagic death in mice","volume":"8","author":"Lv","year":"2017","journal-title":"Oncotarget"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.08.019","article-title":"Autophagy is required for neutrophil-mediated inflammation","volume":"12","author":"Bhattacharya","year":"2015","journal-title":"Cell Rep"},{"key":"B30","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jaci.2016.05.011","article-title":"Inflammatory mechanisms in patients with chronic obstructive pulmonary disease","volume":"138","author":"Barnes","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2024.1289259","article-title":"Sex-differences in COPD: from biological mechanisms to therapeutic considerations","volume":"11","author":"Milne","year":"2024","journal-title":"Front Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200904-018DS","article-title":"Chronic obstructive pulmonary disease in men and women myths and reality","volume":"6","author":"Camp","year":"2009","journal-title":"Proc Am Thorac Soc"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/jcm6050049","article-title":"Serum profiles of cytokines in Behcet\u2019s disease","volume":"6","author":"Sadeghi","year":"2017","journal-title":"J Clin Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.imlet.2016.12.001","article-title":"An elevated pro-inflammatory cytokines profile in Behcet\u2019s disease: A multiplex analysis","volume":"186","author":"Gholijani","year":"2017","journal-title":"Immunol Lett"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.21772","article-title":"Serum cytokine levels in Beh\u00e7et\u2019s disease","volume":"29","author":"Akkurt","year":"2015","journal-title":"J Clin Lab Anal"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1042\/CS20255452","article-title":"COPD: the role of neutrophils in inflammation, pathophysiology, and as drug targets","volume":"139","author":"Fricker","year":"2025","journal-title":"Clin Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1824596\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:10:21Z","timestamp":1779912621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1824596\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":36,"alternative-id":["10.3389\/fimmu.2026.1824596"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1824596","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]},"article-number":"1824596"}}