Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, Davis Heart Lung Research Institute, Columbus, Ohio.
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
Allergy. 2019 Mar;74(3):535-548. doi: 10.1111/all.13626. Epub 2018 Nov 5.
The pathogenesis of asthma and airway obstruction is the result of an abnormal response to different environmental exposures. The scientific premise of our study was based on the finding that FoxO1 expression is increased in lung macrophages of mice after allergen exposure and human asthmatic patients. Macrophages are capable of switching from one functional phenotype to another, and it is important to understand the mechanisms involved in the transformation of macrophages and how their cellular function affects the peribronchial stromal microenvironment.
We employed a murine asthma model, in which mice were treated by intranasal insufflation with allergens for 2-8 weeks. We used both a pharmacologic approach using a highly specific FoxO1 inhibitor and genetic approaches using FoxO1 knockout mice (FoxO1 LysMcre). Cytokine level in biological fluids was measured by ELISA and the expression of encoding molecules by NanoString assay and qRT-PCR.
We show that the levels of FoxO1 gene are significantly elevated in the airway macrophages of patients with mild asthma in response to subsegmental bronchial allergen challenge. Transcription factor FoxO1 regulates a pro-asthmatic phenotype of lung macrophages that is involved in the development and progression of chronic allergic airway disease. We have shown that inhibition of FoxO1 induced phenotypic conversion of lung macrophages and downregulates pro-asthmatic and pro-fibrotic gene expression by macrophages, which contribute to airway inflammation and airway remodeling in allergic asthma.
Targeting FoxO1 with its downstream regulator IRF4 is a novel therapeutic target for controlling allergic inflammation and potentially reversing fibrotic airway remodeling.
哮喘和气道阻塞的发病机制是对不同环境暴露的异常反应的结果。我们研究的科学前提是基于这样的发现，即在过敏原暴露后，小鼠肺巨噬细胞中的 FoxO1 表达增加，并且在人类哮喘患者中也是如此。巨噬细胞能够从一种功能表型转变为另一种功能表型，了解巨噬细胞转化所涉及的机制以及它们的细胞功能如何影响支气管周围基质微环境非常重要。
我们采用了一种小鼠哮喘模型，通过鼻腔内吸入过敏原对小鼠进行 2-8 周的处理。我们使用了一种高度特异性的 FoxO1 抑制剂的药理学方法和 FoxO1 敲除小鼠（FoxO1 LysMcre）的遗传方法。通过 ELISA 测量生物体液中的细胞因子水平，并通过 NanoString 分析和 qRT-PCR 测量编码分子的表达。
我们表明，轻度哮喘患者的气道巨噬细胞中 FoxO1 基因的水平在亚段支气管过敏原刺激下显著升高。转录因子 FoxO1 调节肺巨噬细胞的促哮喘表型，参与慢性变应性气道疾病的发生和发展。我们已经表明，FoxO1 的抑制诱导了肺巨噬细胞的表型转化，并下调了巨噬细胞的促哮喘和促纤维化基因表达，这有助于变应性哮喘中的气道炎症和气道重塑。
用其下游调节因子 IRF4 靶向 FoxO1 是控制变应性炎症和潜在逆转纤维化气道重塑的一种新的治疗靶点。
