背景:钙卫蛋白,一种钙结合蛋白,在炎症中起着至关重要的作用,并与各种炎症性疾病有关,包括哮喘.然而,它对类固醇低反应性的调节和影响,尤其是严重的哮喘,仍然知之甚少。
方法:本研究使用体外和体内模型研究了IL-17对钙卫蛋白(S100A8和S100A9)的调节及其在类固醇低反应性中的作用。在健康对照和严重哮喘患者的原发性支气管成纤维细胞中评估钙卫蛋白的表达,以及在屋尘螨(HDM)过敏原和环状di-GMP(cdiGMP)佐剂诱导的类固醇低反应性肺部炎症的小鼠模型中。检测了IL-17A刺激对支气管上皮细胞和成纤维细胞中钙卫蛋白表达和类固醇反应标志物的影响。此外,帕喹莫德的治疗潜力,钙卫蛋白抑制剂,在减轻小鼠模型中气道炎症和恢复类固醇反应特征方面进行了评价.
结果:结果表明,与健康对照相比,哮喘支气管成纤维细胞中钙卫蛋白的表达上调,以及在难治性哮喘样本与非难治性哮喘相比。IL-17刺激在肺上皮细胞和成纤维细胞中诱导钙卫蛋白表达和失调的糖皮质激素应答特征。用帕喹莫德治疗可逆转IL-17诱导的类固醇症状失调,表明钙卫蛋白参与了这一过程。在HDM/cdiGMP小鼠模型中,paquinimod显著减轻气道炎症和高反应性,并恢复了类固醇反应特征,而地塞米松的疗效有限.机械上,paquinimod抑制钙卫蛋白下游的MAPK/ERK和NF-κB通路,导致肺部炎症减少。
结论:这些发现突出显示钙卫蛋白在类固醇低反应性哮喘中作为IL-17调节的潜在治疗靶点。靶向钙卫蛋白可能提供一种有希望的方法来减轻严重哮喘的气道炎症和恢复类固醇反应性。需要进一步研究以探索其在临床环境中的治疗潜力,并阐明其在类固醇作用机制中的更广泛含义。
BACKGROUND: Calprotectin, a calcium-binding protein, plays a crucial role in inflammation and has been associated with various inflammatory diseases, including asthma. However, its regulation and impact on steroid hyporesponsiveness, especially in severe asthma, remain poorly understood.
METHODS: This study investigated the regulation of calprotectin proteins (S100A8 and S100A9) by IL-17 and its role in steroid hyporesponsiveness using in vitro and in vivo models. Calprotectin expression was assessed in primary bronchial fibroblasts from healthy controls and severe asthmatic patients, as well as in mouse models of steroid hyporesponsive lung inflammation induced by house dust mite (HDM) allergen and cyclic-di-GMP (cdiGMP) adjuvant. The effects of IL-17A stimulation on calprotectin expression and steroid response markers in bronchial epithelial and fibroblast cells were examined. Additionally, the therapeutic potential of paquinimod, a calprotectin inhibitor, in mitigating airway inflammation and restoring steroid response signatures in the mouse model was evaluated.
RESULTS: The results demonstrated upregulation of calprotectin expression in asthmatic bronchial fibroblasts compared to healthy controls, as well as in refractory asthma samples compared to non-refractory asthma. IL-17 stimulation induced calprotectin expression and dysregulated glucocorticoid response signatures in lung epithelial and fibroblast cells. Treatment with paquinimod reversed IL-17-induced dysregulation of steroid signatures, indicating the involvement of calprotectin in this process. In the HDM/cdiGMP mouse model, paquinimod significantly attenuated airway inflammation and hyperresponsiveness, and restored steroid response signatures, whereas dexamethasone showed limited efficacy. Mechanistically, paquinimod inhibited MAPK/ERK and NF-κB pathways downstream of calprotectin, leading to reduced lung inflammation.
CONCLUSIONS: These findings highlight calprotectin as a potential therapeutic target regulated by IL-17 in steroid hyporesponsive asthma. Targeting calprotectin may offer a promising approach to alleviate airway inflammation and restore steroid responsiveness in severe asthma. Further investigations are warranted to explore its therapeutic potential in clinical settings and elucidate its broader implications in steroid mechanisms of action.