{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:17:20Z","timestamp":1785442640470,"version":"3.56.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2020-120336RB-I00"],"award-info":[{"award-number":["PID2020-120336RB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2023-152677OB-I00"],"award-info":[{"award-number":["PID2023-152677OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI21\/00220"],"award-info":[{"award-number":["PI21\/00220"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FI19\/00033"],"award-info":[{"award-number":["FI19\/00033"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CP21\/00025"],"award-info":[{"award-number":["CP21\/00025"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["PROMETEO\/2019\/032"],"award-info":[{"award-number":["PROMETEO\/2019\/032"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["CIPROM\/2022\/45"],"award-info":[{"award-number":["CIPROM\/2022\/45"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic obstructive pulmonary disease (COPD) is mainly caused by long-term exposure to cigarette smoke. Since systemic inflammation is an important component of COPD pathophysiology, its characterization is essential for developing new biomarkers and pharmacological approaches. We have previously reported CXCL16\/CXCR6 axis upregulation, a key element of leukocyte trafficking in COPD. Given the paucity of data on early-stage COPD patients (GOLD 1), we investigated CXCL16\/CXCR6 axis expression in this population and in individuals at risk for developing COPD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Blood samples were collected from 27 GOLD 1 patients, 27 symptomatic smokers with normal lung function (pre-COPD), and 14 non-smokers. CXCR6 expression was assessed in platelets, leukocytes, and leukocyte-platelet aggregates by flow cytometry. Plasma CXCL16 levels were measured by ELISA and lung function by spirometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CXCL16 plasma levels and CXCR6 expression on platelets, classical monocytes, B-cells, and leukocyte-platelet aggregates were higher in GOLD 1 patients than in non-smokers and pre-COPD subjects. While CXCR6 expression was similar between the pre-COPD group and non-smokers, plasma levels of CXCL16 were higher in the former. Finally, CXCL16\/CXCR6 axis expression negatively correlated with FEV1\/FVC ratio.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This pilot study provides the first evidence that the CXCL16\/CXCR6 axis is upregulated in early-COPD development. Increased CXCL16 plasma levels in GOLD 1 patients and pre-COPD subjects suggest CXCL16 as a potential peripheral biomarker of early COPD development. Given the importance of the CXCL16\/CXCR6 axis in leukocyte trafficking, it may emerge as a druggable target to attenuate lung immune cell infiltration and prevent COPD development and progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1636360","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T05:44:35Z","timestamp":1752126275000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CXCL16\/CXCR6 axis arises as a potential peripheral biomarker of early COPD development \u2013 results from a pilot study"],"prefix":"10.3389","volume":"12","author":[{"given":"Patrice","family":"Marques","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Bocigas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Domingo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Francisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Tarras\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Piqueras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Signes-Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cruz","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Jesus","family":"Sanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.3390\/life13061299","article-title":"Cardiovascular diseases in COPD: From diagnosis and prevalence to therapy.","volume":"13","author":"Papaporfyriou","year":"2023","journal-title":"Life (Basel)."},{"key":"B2","year":"2024","journal-title":"Global strategy for prevention, diagnosis and management of COPD: 2024 report."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3449","DOI":"10.3390\/jcm13123449","article-title":"Immunosenescence and Inflammation in chronic obstructive pulmonary disease: A systematic review.","volume":"13","author":"Ramos Jesus","year":"2024","journal-title":"J Clin Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"704173","DOI":"10.3389\/fimmu.2021.704173","article-title":"New pharmacological tools to target leukocyte trafficking in lung disease.","volume":"12","author":"Belchamber","year":"2021","journal-title":"Front Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3855","DOI":"10.3390\/jcm13133855","article-title":"CRP, fibrinogen, white blood cells, and blood cell indices as prognostic biomarkers of future COPD exacerbation frequency: The TIE cohort study.","volume":"13","author":"Ellingsen","year":"2024","journal-title":"J Clin Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s12989-022-00503-9","article-title":"Pro-thrombotic changes associated with exposure to ambient ultrafine particles in patients with chronic obstructive pulmonary disease: Roles of lipid peroxidation and systemic inflammation.","volume":"19","author":"Wang","year":"2022","journal-title":"Part Fibre Toxicol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"4812","DOI":"10.21037\/jtd-20-1580","article-title":"Inflammatory parameters and pulmonary biomarkers in smokers with and without chronic obstructive pulmonary disease (COPD).","volume":"13","author":"Andreeva","year":"2021","journal-title":"J Thorac Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.3390\/diagnostics10121029","article-title":"Combination of systemic inflammatory biomarkers in assessment of chronic obstructive pulmonary disease: Diagnostic performance and identification of networks and clusters.","volume":"10","author":"Hlap\u010di\u0107","year":"2020","journal-title":"Diagnostics (Basel)."},{"key":"B9","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1080\/15412555.2022.2162377","article-title":"Association between galectin-13 expression and eosinophilic airway inflammation in chronic obstructive pulmonary disease.","volume":"20","author":"Yi","year":"2023","journal-title":"COPD."},{"key":"B10","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1183\/23120541.00068-2021","article-title":"Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.","volume":"7","author":"Balasubramanian","year":"2021","journal-title":"ERJ Open Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.3389\/fimmu.2017.01766","article-title":"Cigarette smoke increases endothelial CXCL16-leukocyte CXCR6 adhesion in vitro and in vivo. Potential consequences in chronic obstructive pulmonary disease.","volume":"8","author":"Marques","year":"2017","journal-title":"Front Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1183\/09031936.00088209","article-title":"Systemic inflammatory markers in COPD: Results from the Bergen COPD cohort study.","volume":"35","author":"Eagan","year":"2010","journal-title":"Eur Respir J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1441637","DOI":"10.3389\/fimmu.2024.1441637","article-title":"Key role of activated platelets in the enhanced adhesion of circulating leucocyte-platelet aggregates to the dysfunctional endothelium in early-stage COPD.","volume":"15","author":"Marques","year":"2024","journal-title":"Front Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2300239","DOI":"10.1183\/13993003.00239-2023","article-title":"Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary.","volume":"61","author":"Agust\u00ed","year":"2023","journal-title":"Eur Respir J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e70","DOI":"10.1164\/rccm.201908-1590ST","article-title":"Standardization of spirometry 2019 update. An official american thoracic society and European respiratory society technical statement.","volume":"200","author":"Graham","year":"2019","journal-title":"Am J Respir Crit Care Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"112460","DOI":"10.1016\/j.biopha.2021.112460","article-title":"Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players.","volume":"145","author":"Marques","year":"2022","journal-title":"Biomed Pharmacother."},{"key":"B17","doi-asserted-by":"publisher","first-page":"6362","DOI":"10.4049\/jimmunol.172.10.6362","article-title":"The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10.","volume":"172","author":"Abel","year":"2004","journal-title":"J Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1022136","DOI":"10.3389\/fimmu.2022.1022136","article-title":"CXCR6 expressing T cells: Functions and role in the control of tumors.","volume":"13","author":"Mabrouk","year":"2022","journal-title":"Front Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"19480","DOI":"10.1038\/s41598-020-76556-7","article-title":"The effect of smoking on chronic inflammation, immune function and blood cell composition.","volume":"10","author":"Elisia","year":"2020","journal-title":"Sci Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1186\/s12931-021-01737-5","article-title":"An updated overview of e-cigarette impact on human health.","volume":"22","author":"Marques","year":"2021","journal-title":"Respir Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3715","DOI":"10.3390\/molecules27123715","article-title":"Effects of smoking on inflammatory-related cytokine levels in human serum.","volume":"27","author":"Wang","year":"2022","journal-title":"Molecules."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.1093\/cvr\/cvy135","article-title":"Functional role of endothelial CXCL16\/CXCR6-platelet-leukocyte axis in angiotensin II-associated metabolic disorders.","volume":"114","author":"Collado","year":"2018","journal-title":"Cardiovasc Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.clnu.2013.01.008","article-title":"Associations of CXCL16\/CXCR6 with carotid atherosclerosis in patients with metabolic syndrome.","volume":"32","author":"Lv","year":"2013","journal-title":"Clin Nutr."},{"key":"B24","author":"Swinscow","year":"1997","journal-title":"Statistics at square one."},{"key":"B25","doi-asserted-by":"publisher","first-page":"767","DOI":"10.2353\/ajpath.2007.061177","article-title":"CC chemokine receptor 5 and CXC chemokine receptor 6 expression by lung CD8+ cells correlates with chronic obstructive pulmonary disease severity.","volume":"171","author":"Freeman","year":"2007","journal-title":"Am J Pathol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1636360\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T13:39:08Z","timestamp":1752154748000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1636360\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,9]]},"references-count":25,"alternative-id":["10.3389\/fmed.2025.1636360"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1636360","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,9]]},"article-number":"1636360"}}