{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:33:26Z","timestamp":1788287606185,"version":"build-2803163510"},"reference-count":118,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["1R35HL139726, 1P01HL152961-01"],"award-info":[{"award-number":["1R35HL139726, 1P01HL152961-01"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["U24AG092191"],"award-info":[{"award-number":["U24AG092191"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Trisomy 21 (T21) results in Down syndrome (DS), a condition associated with a high prevalence of pulmonary complications. Pulmonary hypertension (PH) is a significant comorbidity in individuals with T21. Inflammation is a well-established driver of PH, and growing evidence implicates platelets as active contributors to inflammatory-mediated pulmonary vascular disease and PH. In T21, increased interferon (IFN) signaling resulting from an additional IFN receptor gene locus contributes to immune dysregulation, and interactions between platelet activation and IFN signaling may promote thromboinflammatory pathways associated with vascular disease. To determine whether platelet activation is altered in T21, we first measured platelet activation by flow cytometry in individuals with T21 and age-matched controls. We then utilized the Dp16 mouse model of down syndrome to investigate IFN-dependent mechanisms. WT, Dp16, and Dp162xIfnrs mice 7-9 weeks of age were exposed to 10% hypobaric hypoxia for 3 or 21 days or remained at Denver altitude. Platelet activation was measured by flow cytometry. Lungs were collected to measure PF4 by ELISA and lung platelets by IHC. Vascular remodeling was measured by IHC staining of muscularized small vessels. PH was measured by RSVP and RV hypertrophy (RVH). Baseline and agonist-induced platelet activation were increased in individuals with T21, as evidenced by elevated platelet P-selectin expression and activated \u03b1IIb\u03b23. To investigate the immunoregulatory mechanisms underlying T21-associated PH, we utilized the Dp16 mouse model of Down syndrome in a chronic hypoxia model of PH. Consistent with our human findings, baseline, agonist-induced, and hypoxia-induced P-selectin and \u03b1IIb\u03b23 activation were elevated in Dp16 mice compared with wild-type (WT). Circulating PF4 and soluble GPVI were elevated at baseline and PF4 was further increased in hypoxic Dp16 mice. Lung PF4 levels were also increased at baseline and further elevated with hypoxia in Dp16 mice, despite comparable numbers of lung platelets. Dp16 mice demonstrated increased baseline pulmonary vascular remodeling, right ventricular systolic pressure (RVSP), and right ventricular hypertrophy (RVH) with both RVSP and RVH being further exacerbated in hypoxic Dp16 mice. Normalization of\n                    <jats:italic>Ifnr<\/jats:italic>\n                    copy number attenuated hypoxia-induced platelet activation and lung PF4 accumulation. Normalization of\n                    <jats:italic>Ifnr<\/jats:italic>\n                    copy number corrected the baseline increase in pulmonary vascular remodeling and restored RVSP to WT levels. RVH remained elevated at baseline and following hypoxia in Dp16\n                    <jats:sub>2xIfnrs<\/jats:sub>\n                    mice, indicating that\n                    <jats:italic>IFNR<\/jats:italic>\n                    signaling does not fully account for cardiopulmonary phenotypes associated with PH. Together, these findings demonstrate that IFN signaling contributes to platelet activation and pulmonary vascular remodeling in Dp16 mice, but does not drive PH severity, suggesting additional mechanisms in the development of T21-associated PH. This work provides novel insight into the role of IFN signaling and platelet activation in Down syndrome -associated pulmonary vascular disease and has potential clinical relevance given the presence of platelet activation in individuals with T21.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1832057","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:56:56Z","timestamp":1779425816000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Interferon receptor gene dosage differentially regulates hypoxia-induced platelet activation and pulmonary hypertension in down syndrome"],"prefix":"10.3389","volume":"17","author":[{"given":"Janelle N.","family":"Posey","sequence":"first","affiliation":[{"name":"Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"Cardiovascular Pulmonary Research 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Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie L.","family":"Archambault","sequence":"additional","affiliation":[{"name":"Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Sul","sequence":"additional","affiliation":[{"name":"Section of Pediatric Critical Care, Department of Pediatrics, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Colon-Hidalgo","sequence":"additional","affiliation":[{"name":"Cardiovascular Pulmonary Research Laboratories, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"School of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva S.","family":"Nozik","sequence":"additional","affiliation":[{"name":"Section of Pediatric Critical Care, Department of Pediatrics, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin M.","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz","place":["Aurora CO, United States"]},{"name":"Department of Pharmacology, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly 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