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Rare mutations in the <jats:italic>SOX17<\/jats:italic> gene and common variants in the enhancer region are thought to predispose to PAH. Central to the PAH pathobiology is lung immune cell recruitment, orchestrated by the overproduction of chemokines (e.g. CXCL10) via the induction of NF-\u03baB. Emerging evidence from murine models of <jats:italic>SOX17<\/jats:italic> impairment suggests perivascular leukocyte accumulation in the lung, likely due to disordered inflammatory mediator expression. Therefore, in the current study we assessed the role of SOX17 deficiency in human pulmonary artery endothelial cells (HPAECs) on selected inflammatory mediator release. Following a semi-quantitative array of 100 cytokines and chemokines, we identified markedly elevated CXCL10 and CXCL11 mRNA and soluble protein release in <jats:italic>SOX17<\/jats:italic>-silenced HPAECs (versus control siRNA-treated cells), driven by excessive NF-\u03baB p65 activity. Further, we show that plasma CXCL10 levels are raised in a small cohort (<jats:italic>n<\/jats:italic>\u2009=\u20093) of carriers of pathogenic <jats:italic>SOX17<\/jats:italic> rare variants versus healthy controls. Finally, <jats:italic>SOX17<\/jats:italic> knockdown HPAEC supernatants mediated the in vitro migration of transfectants expressing CXCR3. Therefore, enhanced lymphocyte migration may be a pathomechanism of PAH due to <jats:italic>SOX17<\/jats:italic> loss, driven by a CXCL10\/CXCL11\/CXCR3 axis.<\/jats:p>","DOI":"10.1038\/s41598-025-16418-2","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T09:18:50Z","timestamp":1759310330000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["SOX17-silenced HPAECs upregulate NF-\u03baB-induced CXCL10 and CXCL11: implications for lymphocyte chemotaxis in SOX17-PAH"],"prefix":"10.1038","volume":"15","author":[{"given":"Abdul S.","family":"Mahomed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Burke-Gaffney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahin","family":"Moledina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quezia K.","family":"Toe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmin","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Quinlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4962-3204","authenticated-orcid":false,"given":"Christopher J.","family":"Rhodes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3749-0341","authenticated-orcid":false,"given":"James E.","family":"Pease","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen John","family":"Wort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"16418_CR1","doi-asserted-by":"publisher","first-page":"2361","DOI":"10.1056\/NEJMra2000348","volume":"385","author":"PM Hassoun","year":"2021","unstructured":"Hassoun, P. 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