SOX17-silenced HPAECs upregulate NF-κB-induced CXCL10 and CXCL11: implications for lymphocyte chemotaxis in SOX17-PAH
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Author(s)
Type
Journal Article
Abstract
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy characterized by extensive pre-capillary arterial remodeling, instigating increased pulmonary vascular resistance and eventual right heart failure. Rare mutations in the SOX17 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-κB. Emerging evidence from murine models of SOX17 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 SOX17-silenced HPAECs (versus control siRNA-treated cells), driven by excessive NF-κB p65 activity. Further, we show that plasma CXCL10 levels are raised in a small cohort (n = 3) of carriers of pathogenic SOX17 rare variants versus healthy controls. Finally, SOX17 knockdown HPAEC supernatants mediated the in vitro migration of transfectants expressing CXCR3. Therefore, enhanced lymphocyte migration may be a pathomechanism of PAH due to SOX17 loss, driven by a CXCL10/CXCL11/CXCR3 axis.
Date Issued
2025-10-01
Date Acceptance
2025-08-14
Citation
Scientific Reports, 2025, 15
ISSN
2045-2322
Publisher
Nature Portfolio
Journal / Book Title
Scientific Reports
Volume
15
Copyright Statement
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Publication Status
Published
Article Number
34262