Abstract：
Asthma is the most prevalent chronic inflammatory disease of the airways in children. The most prevalent phenotype of asthma is eosinophilic asthma, which is driven by a Th2 immune response and can be effectively managed by inhaled corticosteroid therapy. However, there are phenotypes of asthma with Th17 immune response that are insensitive to corticosteroid therapy and manifest a more severe phenotype. The treatment of this corticosteroid-insensitive asthma is currently immature and requires further attention. The objective of this study is to elucidate the regulation of the Hedgehog signaling pathway in Th17 cell differentiation in asthma. The study demonstrated that both Smo and Gli3, key components of the Hedgehog signaling pathway, were upregulated in Th17 polarization in vitro and in a Th17-dominant asthma model in vivo. Inhibiting Smo with a small molecule inhibitor or genetically knocking down Gli3 was found to suppress Th17 polarization. Smo was found to increase in Th1, Th2, Th17 and Treg polarization, while Gli3 specifically increased in Th17 polarization. ChIP-qPCR analyses indicated that Gli3 can directly interact with IL-6 in T cells, inducing STAT3 phosphorylation and promoting Th17 cell differentiation. Furthermore, the study demonstrated a correlation between elevated Gli3 expression and IL-17A and IL-6 expression in children with asthma. In conclusion, the study demonstrated that the Hedgehog signaling pathway plays an important role in the pathogenesis of asthma, as it regulates the differentiation of Th17 cells through the IL-6/STAT3 signaling. This may provide a potential therapeutic target for corticosteroid-insensitive asthma driven by Th17 cells.
摘要：
哮喘是儿童气道中最常见的慢性炎症性疾病。哮喘最普遍的表型是嗜酸性粒细胞性哮喘,这是由Th2免疫反应驱动的，可以通过吸入皮质类固醇治疗有效地管理。然而,有Th17免疫应答的哮喘表型对皮质类固醇治疗不敏感,表现出更严重的表型.这种对皮质类固醇不敏感的哮喘的治疗目前尚不成熟，需要进一步关注。本研究旨在阐明Hedgehog信号通路在哮喘Th17细胞分化中的调控作用。研究表明，Smo和Gli3都是Hedgehog信号通路的关键组成部分，在体外Th17极化和体内Th17显性哮喘模型中上调。发现用小分子抑制剂抑制Smo或基因敲除Gli3可以抑制Th17极化。发现Smo在Th1，Th2，Th17和Treg极化中增加，而Gli3在Th17极化中特异性增加。ChIP-qPCR分析表明，Gli3可以直接与T细胞中的IL-6相互作用，诱导STAT3磷酸化并促进Th17细胞分化。此外，该研究表明哮喘患儿Gli3表达升高与IL-17A和IL-6表达之间存在相关性.总之,研究表明,Hedgehog信号通路在哮喘的发病机制中起着重要作用,因为它通过IL-6/STAT3信号调节Th17细胞的分化。这可能为Th17细胞驱动的皮质类固醇不敏感哮喘提供潜在的治疗靶标。
