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IRF4 Participates in Pulmonary Fibrosis Induced by Silica Particles through Regulating Macrophage Polarization and Fibroblast Activation

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Abstract

Long-term exposure to silica dust can cause silicosis, which is characterized by chronic progressive inflammatory injury, fibroblast activation, and the deposition of extracellular matrix. IRF4 is involved in immune response. However, the potential regulation of IRF4 in silicosis and pulmonary fibrosis remains largely unexplored. In this study, RNA-seq analysis identified the upregulated expression of IRF4 in fibrotic lung tissues of mice exposed to silica particles. And we verified the increased expression of IRF4 in SiO2-treated macrophages and TGF-β1-treated fibroblasts. We further found that the down-regulation of IRF4 impeded the macrophage polarization and the release of pro-fibrotic factors. Moreover, the down-regulation of IRF4 alleviated the migration, invasion, and the expression of fibrotic molecules in fibroblasts. Using ChIP-qPCR assay, we confirmed that IRF4 regulated the transcriptional activity of the IL-17A promoter, thus stimulated fibroblast activation, migration and invasion. In vivo experiment, the AAV-siIRF4 was designed to interfere with the expression of IRF4 in lung tissues of mice exposed to silica particles. Whole blood, bronchoalveolar lavage fluid and lung tissues were obtained from mice at 7, 14, 28 and 56 days after silica exposure. The results showed that the leukocyte content and inflammatory factors reached a peak at day 14 and remained peak for a long time after IRF4 knockdown. Furthermore, the fibrotic responses of mouse lung tissues were alleviated after IRF4 knockdown. Our study explored the important roles of IRF4 in inflammatory and fibrotic responses, which provided a new target for the treatment of silicosis and pulmonary fibrosis.

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Funding

This work was supported by the National Natural Science Foundation of China [81803204].

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Authors and Affiliations

  1. School of Public Health, Xuzhou Medical University, Xuzhou, 221004, China

    Biyang Jiao, Qianyi Zhang, Chunmeng Jin, Hongmin Yu & Qiuyun Wu

  2. Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou, 221004, China

    Qiuyun Wu

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Contributions

Biyang Jiao: Conceptualization, Investigation, Methodology, and Writing—original draft; Qianyi Zhang: Investigation, Methodology, and Validation; Chunmeng Jin: Methodology and Validation; Hongmin Yu: Investigation and Writing—review & editing; Qiuyun Wu: Conceptualization, Funding acquisition, Methodology, Writing—original draft and Writing—review & editing. All authors revised and approved the final manuscript.

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Correspondence to Qiuyun Wu.

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Jiao, B., Zhang, Q., Jin, C. et al. IRF4 Participates in Pulmonary Fibrosis Induced by Silica Particles through Regulating Macrophage Polarization and Fibroblast Activation. Inflammation 47, 45–59 (2024). https://doi.org/10.1007/s10753-023-01890-7

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