Silica-exposed macrophages-secreted exosomal miR125a-5p induces Th1/Th2 and Treg/Th17 cell imbalance and promotes fibroblast transdifferentiation.

Abstract

Until now, the specific pathogenesis of silicosis is not clear. Exosomal miRNAs, as a newly discovered intercellular communication medium, play an important role in many diseases. Our previous research found that serum exosomal miR125a-5p was increased in silicosis patients by miRNAs high-throughput sequencing. TRAF6, is a target gene of miR125a-5p, which is involved in T-cell differentiation. Furthermore, results from animal study indicate that knockdown of miR-125a-5p can regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6. However, the level of serum exosomal miR125a-5p in silicosis patients has not been reported, the role of macrophages-secreted exosomal miR-125a-5p in regulating T cell differentiation to promote fibroblast transdifferentiation (FMT) remains unknown. In this study, the levels of serum exosomal miR125a-5p and serum TGF-β1, IL-17A, IL-4 cytokines in silicosis patients were elevated, with the progression of silicosis, the level of serum exosomal miR125a-5p and serum IL-4 were increased; thus, the serum level of IFN-γ was negatively correlated with the progression of silicosis. In vitro, the levels of miR125a-5p in macrophages, exosomes, and T cells stimulated by silica were significantly increased. When the mimic was transfected into T cells, which directly suppressed TRAF6 and caused the imbalance of T cells differentiation, induced FMT. To sum up, these results indicate that exosomal miR-125a-5p may by targeting TRAF6 of T cells, induces the activation and apoptosis of T cells and the remodeling of Th1/Th2 and Th17/Tregs distribution, ultimately promotes FMT. Suggesting that exosomal miR-125a-5p may be a potential therapeutic target for silicosis.

• Authors: Mingcui Ding, Chengpeng Zhang, Wei Wang, Pengpeng Wang, Yangqing Pei, Na Wang, Shan Huang, Changfu Hao, Wu Yao
• Journal: Ecotoxicology and environmental safety (Ecotoxicol Environ Saf) Vol. 267 Pg. 115647 (Nov 15 2023) ISSN: 1090-2414 [Electronic] Netherlands
• PMID: 37918332 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Silicon Dioxide
• Interleukin-4
• TNF Receptor-Associated Factor 6
• MicroRNAs

Topics

• Animals
• Humans
• T-Lymphocytes, Regulatory
• Silicon Dioxide (toxicity)
• Cell Transdifferentiation
• Interleukin-4
• TNF Receptor-Associated Factor 6
• Th17 Cells
• Silicosis (genetics)
• MicroRNAs (genetics)
• Fibroblasts