肺成纤维细胞来源的干细胞因子通过增加IL-17A的产生促进中性粒细胞哮喘。

Jheng-Syuan Shao,Alan C Lai,Wei-Chang Huang,Ko-Chien Wu,Po-Yu Chi,Yao-Ming Chang,Ya-Jen Chang
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引用次数: 0

摘要

第3组先天淋巴样细胞(ILC3s)在嗜中性粒细胞哮喘的发病机制中起着重要的作用。然而,肺中支持ILC3反应的调节机制仍不清楚。本研究表明,哮喘患者的干细胞因子(SCF)表达显著升高,并与IL-17A和MPO表达呈正相关。值得注意的是,我们发现ILC3是肺SCF的主要il - 17a产生应答者。在小鼠中,SCF与IL-1β/IL-23协同作用,增强肺ILC3激活和中性粒细胞炎症。机制上,SCF促进ILC3增殖和细胞因子的产生。转录组学分析显示,SCF处理上调了与增殖和Th17分化相关的基因,与AKT和STAT3信号通路的增加有关。相反,在小鼠中性粒细胞哮喘模型中,缺乏SCF受体c-Kit可减少ILC3的增殖和IL-17A的产生,从而改善气道高反应性(AHR)和中性粒细胞炎症。此外,成纤维细胞中SCF的基因缺失揭示了成纤维细胞是肺中ILC3激活的SCF的主要来源。此外,给予伊马替尼(一种c-Kit抑制剂)可以缓解LPS、空气污染或卵清蛋白/LPS诱导的AHR和中性粒细胞炎症。我们的研究结果阐明了SCF/c-Kit信号在中性粒细胞炎症期间ILC3反应中的积极调节作用,为中性粒细胞哮喘提供了潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pulmonary fibroblast-derived stem cell factor promotes neutrophilic asthma by augmenting IL-17A production from ILC3s.
Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.
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