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<p>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 <i>SOX17</i> 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 <i>SOX17</i> 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 <i>SOX17</i>-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 (<i>n</i> = 3) of carriers of pathogenic <i>SOX17</i> rare variants versus healthy controls. Finally, <i>SOX17</i> knockdown HPAEC supernatants mediated the in vitro migration of transfectants expressing CXCR3. Therefore, enhanced lymphocyte migration may be a pathomechanism of PAH due to <i>SOX17</i> loss, driven by a CXCL10/CXCL11/CXCR3 axis.</p>

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SOX17-silenced HPAECs upregulate NF-κB-induced CXCL10 and CXCL11: implications for lymphocyte chemotaxis in SOX17-PAH

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月1日

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  • Abdul S. Mahomed,
  • Anne Burke-Gaffney,
  • Shahin Moledina,
  • Quezia K. Toe,
  • Dongmin Shao,
  • Gregory J. Quinlan,
  • Christopher J. Rhodes,
  • James E. Pease,
  • Stephen John Wort

摘要

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.