阻断组蛋白去乙酰化酶活性作为变应性鼻炎患者上皮屏障缺陷的新靶点。
Blocking histone deacetylase activity as a novel target for epithelial barrier defects in patients with allergic rhinitis.
机构信息
Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
出版信息
J Allergy Clin Immunol. 2019 Nov;144(5):1242-1253.e7. doi: 10.1016/j.jaci.2019.04.027. Epub 2019 May 11.
BACKGROUND
A defective epithelial barrier is found in patients with allergic rhinitis (AR) and asthma; however, the underlying mechanisms remain poorly understood. Histone deacetylase (HDAC) activity has been identified as a crucial driver of allergic inflammation and tight junction dysfunction.
OBJECTIVE
We investigated whether HDAC activity has been altered in patients with AR and in a mouse model of house dust mite (HDM)-induced allergic asthma and whether it contributed to epithelial barrier dysfunction.
METHODS
Primary nasal epithelial cells of control subjects and patients with AR were cultured at the air-liquid interface to study transepithelial electrical resistance and paracellular flux of fluorescein isothiocyanate-dextran (4 kDa) together with mRNA expression and immunofluorescence staining of tight junctions. Air-liquid interface cultures were stimulated with different concentrations of JNJ-26481585, a broad-spectrum HDAC inhibitor. In vivo the effect of JNJ-26481585 on mucosal permeability and tight junction function was evaluated in a mouse model of HDM-induced allergic airway inflammation.
RESULTS
General HDAC activity was greater in nasal epithelial cells of patients with AR and correlated inversely with epithelial integrity. Treatment of nasal epithelial cells with JNJ-26481585 restored epithelial integrity by promoting tight junction expression and protein reorganization. HDM-sensitized mice were treated with JNJ-26481585 to demonstrate the in vivo role of HDACs. Treated mice did not have allergic airway inflammation and had no bronchial hyperreactivity. Moreover, JNJ-26481585 treatment restored nasal mucosal function by promoting tight junction expression.
CONCLUSION
Our findings identify increased HDAC activity as a potential tissue-injury mechanism responsible for dysregulated epithelial cell repair, leading to defective epithelial barriers in AR. Blocking HDAC activity is a promising novel target for therapeutic intervention in patients with airway diseases.
背景
变应性鼻炎（AR）和哮喘患者存在上皮屏障缺陷，但潜在机制仍不清楚。组蛋白去乙酰化酶（HDAC）活性已被确定为过敏炎症和紧密连接功能障碍的关键驱动因素。
目的
我们研究了 AR 患者和屋尘螨（HDM）诱导的变应性哮喘小鼠模型中 HDAC 活性是否发生改变，以及它是否导致上皮屏障功能障碍。
方法
培养对照受试者和 AR 患者的鼻上皮细胞，在气液界面培养以研究跨上皮电阻和荧光素异硫氰酸酯-葡聚糖（4 kDa）的旁细胞通量，同时检测紧密连接的 mRNA 表达和免疫荧光染色。用不同浓度的 JNJ-26481585（一种广谱 HDAC 抑制剂）刺激气液界面培养物。在体内，通过评估 JNJ-26481585 对 HDM 诱导的变应性气道炎症中黏膜通透性和紧密连接功能的影响，研究其在 HDM 诱导的变应性气道炎症小鼠模型中的作用。
结果
AR 患者鼻上皮细胞中的总 HDAC 活性更高，与上皮完整性呈负相关。用 JNJ-26481585 处理鼻上皮细胞可通过促进紧密连接的表达和蛋白重排来恢复上皮完整性。用 JNJ-26481585 处理 HDM 致敏的小鼠以证明 HDAC 在体内的作用。治疗组小鼠没有变应性气道炎症，也没有支气管高反应性。此外，JNJ-26481585 治疗通过促进紧密连接的表达来恢复鼻黏膜功能。
结论
我们的研究结果表明，HDAC 活性增加可能是导致上皮细胞修复失调、导致 AR 上皮屏障缺陷的组织损伤机制。抑制 HDAC 活性是治疗气道疾病患者的一种有前途的新靶点。
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