Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, 250014, China.
Inflamm Res. 2022 Aug;71(7-8):873-885. doi: 10.1007/s00011-022-01585-z. Epub 2022 Jun 7.
Fos-related antigen-2 (Fra-2) is a transcription factor belonging to the activator protein 1 (AP-1) family, which is associated with many chronic airway diseases such as asthma. Alternatively activated (M2) macrophages are associated with Fra2 in airway diseases such as pulmonary fibrosis. However, there is no specific study that explores the relationship between M2 macrophages and Fra2 in asthma.
We hypothesized that a potential mechanism of allergic asthma could be that Fra2 is highly expressed in M2 macrophages through JAK3-STAT5 and facilitates the production of downstream T-helper 2 (Th2) cytokines, thus promoting the pathogenesis of asthma.
Peripheral venous blood and airway tissue samples of patients with asthma and controls were obtained. Moreover, a C57BL/6 mouse model of asthma was established. Fra2 expression was detected using immunohistochemistry and immunofluorescence. Macrophages were obtained by flow sorting, and expression of the JAK3-STAT5-Fra2 signaling pathway was determined using PCR and western blotting. Enzyme-linked immunosorbent assay was used to determine M2 macrophage-associated Th2-type cytokine levels.
Fra2 was highly expressed in patients with asthma and asthmatic mice. The JAK3-STAT5 was a signal pathway related to the high expression of Fra2 in M2 macrophages. Moreover, we found that Fra2 could affect the production of Th2 cytokines downstream of M2 macrophages, including interleukin 4 (IL-4) and IL-13.
M2 macrophages could promote airway inflammation through JAK3-STAT5-Fra2 to induce allergic asthma. Our study offers a new insight to further understand the pathogenesis of asthma and also provides a new direction for targeted treatment.
Fos 相关抗原-2（Fra-2）是一种转录因子，属于激活蛋白 1（AP-1）家族，与哮喘等许多慢性气道疾病有关。在肺纤维化等气道疾病中，替代激活（M2）巨噬细胞与 Fra2 相关。然而，目前尚无专门研究探讨哮喘中 M2 巨噬细胞与 Fra2 之间的关系。
我们假设过敏性哮喘的一个潜在机制可能是 Fra2 通过 JAK3-STAT5 在 M2 巨噬细胞中高表达，并促进下游辅助性 T 细胞 2（Th2）细胞因子的产生，从而促进哮喘的发病机制。
收集哮喘患者和对照者的外周静脉血和气道组织样本，此外还建立了 C57BL/6 哮喘小鼠模型。通过免疫组织化学和免疫荧光检测 Fra2 的表达。通过流式细胞分选获得巨噬细胞，并通过 PCR 和 Western blot 检测 JAK3-STAT5-Fra2 信号通路的表达。酶联免疫吸附试验用于测定 M2 巨噬细胞相关 Th2 型细胞因子水平。
Fra2 在哮喘患者和哮喘小鼠中高表达。JAK3-STAT5 是 Fra2 在 M2 巨噬细胞中高表达的相关信号通路。此外，我们发现 Fra2 可影响 M2 巨噬细胞下游 Th2 细胞因子的产生，包括白细胞介素 4（IL-4）和白细胞介素 13（IL-13）。
M2 巨噬细胞可通过 JAK3-STAT5-Fra2 促进气道炎症，从而诱导过敏性哮喘。本研究为进一步了解哮喘的发病机制提供了新的视角，并为靶向治疗提供了新的方向。
