Calprotectin is regulated by IL-17A and induces steroid hyporesponsiveness in asthma.

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-11-01 Epub Date: 2024-08-30 DOI:10.1007/s00011-024-01937-x
Narjes Saheb Sharif-Askari, Bushra Mdkhana, Shirin Hafezi, Bariaa A Khalil, Baraa Khalid Al-Sheakly, Hala Halwani, Fatemeh Saheb Sharif-Askari, Rabih Halwani
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Abstract

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.

Conclusion: 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.

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钙蛋白受 IL-17A 调节,并诱导哮喘患者对类固醇的低反应性。
背景:钙粘蛋白是一种钙结合蛋白,在炎症中起着至关重要的作用,与包括哮喘在内的多种炎症性疾病有关。然而,人们对钙粘蛋白的调控及其对类固醇低反应性的影响,尤其是对重症哮喘的影响仍知之甚少:本研究使用体外和体内模型研究了 IL-17 对钙粘蛋白(S100A8 和 S100A9)的调控及其在类固醇低反应性中的作用。在健康对照组和严重哮喘患者的原发性支气管成纤维细胞中,以及在由屋尘螨(HDM)过敏原和环二-GMP(cdiGMP)佐剂诱导的类固醇低反应性肺部炎症小鼠模型中,对钙蛋白表达进行了评估。研究还考察了 IL-17A 刺激对支气管上皮细胞和成纤维细胞中钙蛋白表达和类固醇反应标记物的影响。此外,还评估了钙蛋白抑制剂帕喹莫德(paquinimod)在减轻气道炎症和恢复小鼠模型类固醇反应特征方面的治疗潜力:结果:研究结果表明,与健康对照组相比,哮喘支气管成纤维细胞中钙蛋白表达上调;与非难治性哮喘相比,难治性哮喘样本中钙蛋白表达上调。IL-17刺激可诱导肺上皮细胞和成纤维细胞中钙蛋白的表达和糖皮质激素反应特征的失调。用帕奎尼莫德治疗可逆转IL-17诱导的类固醇特征失调,表明钙调蛋白参与了这一过程。在 HDM/cdiGMP 小鼠模型中,paquinimod 能显著减轻气道炎症和高反应性,恢复类固醇反应特征,而地塞米松的疗效有限。从机制上讲,paquinimod抑制了钙粘蛋白下游的MAPK/ERK和NF-κB通路,从而减轻了肺部炎症:这些发现强调了钙粘蛋白是类固醇低反应性哮喘中受 IL-17 调控的潜在治疗靶点。以钙蛋白为靶点可能是缓解气道炎症和恢复重症哮喘患者类固醇反应性的一种有前景的方法。还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广泛影响。
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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
期刊最新文献
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