CXCR3A and its IFN-inducible ligands CXCL9 and CXCL10 regulate vascular remodelling and fibroblast motility. IL‑13 is a pro‑fibrotic cytokine implicated in the pathogenies of inflammatory and fibro-proliferative conditions. Previous work from our lab has shown that CXCR3A is negatively regulated by IL-13 and is necessary for the basal regulation of the IL-13 receptor subunit IL-13Rα2. This study investigates the regulation of fibroblast phenotype, function and downstream IL-13 signalling by CXCR3A in vitro. CXCR3A was overexpressed via transient transfection. CXCR3A^-/- lung fibroblastswere isolated for functional analysis. Additionally, the contribution of CXCR3A to tissue remodelling following acute lung injury was assessed in vivo using wild type (WT) and CXCR3^-/- mice challenged with IL-13. CXCR3 and IL‑13Rα2 displayed a reciprocal relationship following stimulation with either IL-13 or CXCR3 ligands. CXCR3A reduced expression of fibroblast activation makers, soluble collagen production and proliferation. CXCR3A enhanced the basal expression of pERK1/2 while inducing IL-13 mediated down‑regulation of NFκB‑p65. CXCR3A^-/- pulmonary fibroblasts were increasingly proliferative and displayed reduced contractility and α‑smooth muscle actin expression. IL-13 challenge regulated expression of the CXCR3 ligands and soluble IL-13Rα2 levels in lungs and broncho‑alveolar lavage fluid (BALF) of WT mice, this response was absent in CXCR3^-/- mice. Alveolar macrophage accumulation and expression of genes involved in lung remodelling was increased in CXCR3^-/- mice. We conclude that CXCR3A is a central anti-fibrotic factor in pulmonary fibroblasts, limiting fibroblast activation and reducing ECM production. Therefore targeting of CXCR3A may be a novel approach to regulate fibroblast activity in lung fibrosis and remodelling.

中文翻译：

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CXCR3A促进肺成纤维细胞分泌抗纤维化诱饵受体sIL-13Rα2

CXCR3A及其干扰素诱导的配体CXCL9和CXCL10调节血管重塑和成纤维细胞运动。IL-13是一种纤维化前细胞因子，与炎症和纤维增生性疾病的病因有关。我们实验室的先前工作表明，CXCR3A受IL-13负调节，对于IL-13受体亚基IL-13Rα2的基础调节是必需的。这项研究调查了CXCR3A在体外对成纤维细胞表型，功能和下游IL-13信号传导的调节。CXCR3A通过瞬时转染而过表达。CXCR3A ^-/-肺成纤维细胞进行功能分析。另外，使用野生型（WT）和用IL-13激发的CXCR3 ^-/-小鼠体内评估了CXCR3A对急性肺损伤后组织重塑的贡献。在用IL-13或CXCR3配体刺激后，CXCR3和IL-13Rα2表现出相互关系。CXCR3A减少了成纤维细胞激活剂的表达，可溶性胶原蛋白的产生和增殖。CXCR3A增强pERK1 / 2的基础表达，同时诱导IL-13介导的NFκB-p65下调。CXCR3A ^-/-肺成纤维细胞越来越多地增生，并且收缩力和α-平滑肌肌动蛋白表达降低。IL-13挑战了WT小鼠的肺和支气管肺泡灌洗液（BALF）中CXCR3配体的表达和可溶性IL-13Rα2的水平，在CXCR3 ^-/-小鼠中没有这种反应。CXCR3 ^-/-小鼠的肺泡巨噬细胞积累和参与肺重构的基因表达增加。我们得出的结论是，CXCR3A是肺成纤维细胞中的中心抗纤维化因子，限制了成纤维细胞的活化并降低了ECM的产生。因此，靶向CXCR3A可能是一种在肺纤维化和重塑中调节成纤维细胞活性的新方法。