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Alternatively activated macrophages promote airway inflammation through JAK3–STAT5–Fra2 in asthma

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Abstract

Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

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Availability of data and materials

Experimental data related to this study can be obtained from the corresponding author upon reasonable request.

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Funding

This work was funded by the National Natural Science Foundation of China (Grant No. 81770029).

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Authors and Affiliations

  1. Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Siyuan Huang & Jing Wang

  2. 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

    Fen Liu & Liang Dong

Authors
  1. Siyuan Huang
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  2. Jing Wang
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  3. Fen Liu
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  4. Liang Dong
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Correspondence to Liang Dong.

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The authors would like to declare that they have no conflict of interest.

Ethical approval

All studies involving human participants were conducted in accordance with the standards of the Ethics Committee of Shandong Provincial Qianfoshan Hospital. The Institutional Animal Care and Use Committee of Shandong University approved all animal experiments in this study.

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Huang, S., Wang, J., Liu, F. et al. Alternatively activated macrophages promote airway inflammation through JAK3–STAT5–Fra2 in asthma. Inflamm. Res. 71, 873–885 (2022). https://doi.org/10.1007/s00011-022-01585-z

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  • DOI: https://doi.org/10.1007/s00011-022-01585-z

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