IL-37在慢性哮喘中通过IL-24信号通路逆转支气管上皮-间质转化防止气道重塑
2022/09/20
摘要
背景：上皮间质转化（EMT）是慢性哮喘气道重塑的机制之一。白细胞介素（IL）-24与促进组织纤维化有关，在哮喘患者的鼻分泌物和痰中观察到IL-24水平升高。然而，IL-24在哮喘气道重塑中的作用，尤其是在EMT中的作用仍基本未知。我们旨在探讨IL-24在EMT中的作用和机制，并验证IL-37是否能够减轻IL-24诱导的慢性哮喘EMT。
方法：将BEAS-2B细胞暴露于IL-24，通过伤口愈合和迁移实验分析评估细胞迁移。在用IL-24和IL-37刺激细胞后，评估EMT相关生物标志物（E-钙粘蛋白、波形蛋白和α-SMA）的表达。通过鼻内施用屋尘螨（HDM）提取物5周，并且通过鼻内施用si-IL-24和rhIL-37来研究IL-24、IL-37对EMT和气道重塑的影响。
结果：我们观察到IL-24在体外显著增强BEAS-2B细胞的迁移。IL-24通过STAT3和ERK1/2途径促进EMT生物标志物波形蛋白和α-SMA的表达。此外，我们发现IL-37通过阻断ERK1/2和STAT3通路，部分逆转了IL-24诱导的BEAS-2B细胞EMT。类似地，体内结果显示，IL-24在HDM诱导的慢性哮喘模型的气道上皮中过度表达，IL-24沉默或IL-37治疗可逆转EMT生物标志物表达。
结论：总的来说，这些发现表明，IL-37通过ERK1/2和STAT3途径抑制IL-24介导的EMT，减轻HDM诱导的气道重塑，从而为IL-24作为新的治疗靶点和IL-37作为治疗严重哮喘的有前景的药物提供了实验证据。
IL-37 protects against airway remodeling by reversing bronchial epithelial-mesenchymal transition via IL-24 signaling pathway in chronic asthma
Kang-Ni Feng, Ping Meng, Xiao-Ling Zou, Min Zhang, Hai-Ke Li, Hai-Ling Yang, Hong-Tao Li, Tian-Tuo Zhang
Abstract
Background: Epithelial-mesenchymal transition (EMT) is one of the mechanisms of airway remodeling in chronic asthma. Interleukin (IL)-24 has been implicated in the promotion of tissue fibrosis, and increased IL-24 levels have been observed in the nasal secretions and sputum of asthmatic patients. However, the role of IL-24 in asthmatic airway remodeling, especially in EMT, remains largely unknown. We aimed to explore the effect and mechanism of IL-24 on EMT and to verify whether IL-37 could alleviate IL-24-induced EMT in chronic asthma.
Methods: BEAS-2B cells were exposed to IL-24, and cell migration was assessed by wound healing and Transwell assays. The expression of EMT-related biomarkers (E-cadherin, vimentin, and α-SMA) was evaluated after the cells were stimulated with IL-24 with or without IL-37. A murine asthma model was established by intranasal administration of house dust mite (HDM) extracts for 5 weeks, and the effects of IL-24 and IL-37 on EMT and airway remodeling were investigated by intranasal administration of si-IL-24 and rhIL-37.
Results: We observed that IL-24 significantly enhanced the migration of BEAS-2B cells in vitro. IL-24 promoted the expression of the EMT biomarkers vimentin and α-SMA via the STAT3 and ERK1/2 pathways. In addition, we found that IL-37 partially reversed IL-24-induced EMT in BEAS-2B cells by blocking the ERK1/2 and STAT3 pathways. Similarly, the in vivo results showed that IL-24 was overexpressed in the airway epithelium of an HDM-induced chronic asthma model, and IL-24 silencing or IL-37 treatment could reverse EMT biomarker expression.
Conclusions: Overall, these findings indicated that IL-37 mitigated HDM-induced airway remodeling by inhibiting IL-24-mediated EMT via the ERK1/2 and STAT3 pathways, thereby providing experimental evidence for IL-24 as a novel therapeutic target and IL-37 as a promising agent for treating severe asthma.
背景：上皮间质转化（EMT）是慢性哮喘气道重塑的机制之一。白细胞介素（IL）-24与促进组织纤维化有关，在哮喘患者的鼻分泌物和痰中观察到IL-24水平升高。然而，IL-24在哮喘气道重塑中的作用，尤其是在EMT中的作用仍基本未知。我们旨在探讨IL-24在EMT中的作用和机制，并验证IL-37是否能够减轻IL-24诱导的慢性哮喘EMT。
方法：将BEAS-2B细胞暴露于IL-24，通过伤口愈合和迁移实验分析评估细胞迁移。在用IL-24和IL-37刺激细胞后，评估EMT相关生物标志物（E-钙粘蛋白、波形蛋白和α-SMA）的表达。通过鼻内施用屋尘螨（HDM）提取物5周，并且通过鼻内施用si-IL-24和rhIL-37来研究IL-24、IL-37对EMT和气道重塑的影响。
结果：我们观察到IL-24在体外显著增强BEAS-2B细胞的迁移。IL-24通过STAT3和ERK1/2途径促进EMT生物标志物波形蛋白和α-SMA的表达。此外，我们发现IL-37通过阻断ERK1/2和STAT3通路，部分逆转了IL-24诱导的BEAS-2B细胞EMT。类似地，体内结果显示，IL-24在HDM诱导的慢性哮喘模型的气道上皮中过度表达，IL-24沉默或IL-37治疗可逆转EMT生物标志物表达。
结论：总的来说，这些发现表明，IL-37通过ERK1/2和STAT3途径抑制IL-24介导的EMT，减轻HDM诱导的气道重塑，从而为IL-24作为新的治疗靶点和IL-37作为治疗严重哮喘的有前景的药物提供了实验证据。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Respir Res. 2022 Sep 13;23(1):244. doi: 10.1186/s12931-022-02167-7.)
(Respir Res. 2022 Sep 13;23(1):244. doi: 10.1186/s12931-022-02167-7.)
IL-37 protects against airway remodeling by reversing bronchial epithelial-mesenchymal transition via IL-24 signaling pathway in chronic asthma
Kang-Ni Feng, Ping Meng, Xiao-Ling Zou, Min Zhang, Hai-Ke Li, Hai-Ling Yang, Hong-Tao Li, Tian-Tuo Zhang
Abstract
Background: Epithelial-mesenchymal transition (EMT) is one of the mechanisms of airway remodeling in chronic asthma. Interleukin (IL)-24 has been implicated in the promotion of tissue fibrosis, and increased IL-24 levels have been observed in the nasal secretions and sputum of asthmatic patients. However, the role of IL-24 in asthmatic airway remodeling, especially in EMT, remains largely unknown. We aimed to explore the effect and mechanism of IL-24 on EMT and to verify whether IL-37 could alleviate IL-24-induced EMT in chronic asthma.
Methods: BEAS-2B cells were exposed to IL-24, and cell migration was assessed by wound healing and Transwell assays. The expression of EMT-related biomarkers (E-cadherin, vimentin, and α-SMA) was evaluated after the cells were stimulated with IL-24 with or without IL-37. A murine asthma model was established by intranasal administration of house dust mite (HDM) extracts for 5 weeks, and the effects of IL-24 and IL-37 on EMT and airway remodeling were investigated by intranasal administration of si-IL-24 and rhIL-37.
Results: We observed that IL-24 significantly enhanced the migration of BEAS-2B cells in vitro. IL-24 promoted the expression of the EMT biomarkers vimentin and α-SMA via the STAT3 and ERK1/2 pathways. In addition, we found that IL-37 partially reversed IL-24-induced EMT in BEAS-2B cells by blocking the ERK1/2 and STAT3 pathways. Similarly, the in vivo results showed that IL-24 was overexpressed in the airway epithelium of an HDM-induced chronic asthma model, and IL-24 silencing or IL-37 treatment could reverse EMT biomarker expression.
Conclusions: Overall, these findings indicated that IL-37 mitigated HDM-induced airway remodeling by inhibiting IL-24-mediated EMT via the ERK1/2 and STAT3 pathways, thereby providing experimental evidence for IL-24 as a novel therapeutic target and IL-37 as a promising agent for treating severe asthma.
上一篇：
一种新的环烯醚萜苷益母草苷(益母草苷)通过抑制ova诱导的哮喘小鼠2型高细胞因子/趋化因子活性来减轻气道炎症和重塑
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