Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China; Department of Pediatrics, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.
Department of Respiration, Wuxi Children's Hospital, Wuxi, China.
Int Immunopharmacol. 2024 Sep 30;139:112771. doi: 10.1016/j.intimp.2024.112771. Epub 2024 Jul 28.
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.
哮喘是儿童气道最常见的慢性炎症性疾病。哮喘最常见的表型是嗜酸性粒细胞性哮喘，它由 Th2 免疫反应驱动，可以通过吸入皮质类固醇治疗有效地管理。然而，有些哮喘表型存在 Th17 免疫反应，对皮质类固醇治疗不敏感，表现出更严重的表型。这种皮质类固醇不敏感的哮喘的治疗目前还不成熟，需要进一步关注。本研究的目的是阐明 Hedgehog 信号通路在哮喘中 Th17 细胞分化中的调控作用。研究表明，Hedgehog 信号通路的关键组成部分 Smo 和 Gli3 在体外 Th17 极化和体内 Th17 优势型哮喘模型中均上调。用小分子抑制剂抑制 Smo 或基因敲低 Gli3 被发现可以抑制 Th17 极化。Smo 被发现增加了 Th1、Th2、Th17 和 Treg 的极化，而 Gli3 特异性地增加了 Th17 的极化。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，促进 Th17 细胞分化。此外，该研究还表明，哮喘患儿中 Gli3 表达升高与 IL-17A 和 IL-6 表达之间存在相关性。总之，该研究表明 Hedgehog 信号通路在哮喘发病机制中起着重要作用，它通过 IL-6/STAT3 信号通路调节 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一个潜在的治疗靶点。
