Pleural
fibrosis is defined as an excessive deposition of extracellular matrix that results in destruction of the normal pleural tissue architecture and compromised function.
Tuberculous pleurisy,
asbestos injury, and rheumatoid
pleurisy are main causes of pleural
fibrosis. Pleural mesothelial cells (PMCs) play a key role in pleural
fibrosis. However, detailed mechanisms are poorly understood.
Serine/
arginine-rich
protein SRSF6 belongs to a family of highly conserved
RNA-binding
splicing-factor proteins. Based on its known functions, SRSF6 should be expected to play a role in fibrotic diseases. However, the role of SRSF6 in pleural
fibrosis remains unknown. In this study, SRSF6
protein was found to be increased in cells of tuberculous
pleural effusions (TBPE) from patients, and decellularized TBPE,
bleomycin, and TGF-β1 were confirmed to increase SRSF6 levels in PMCs. In vitro, SRSF6 mediated PMC proliferation and synthesis of the main fibrotic
protein COL1A2. In vivo, SRSF6 inhibition prevented mouse experimental pleural
fibrosis. Finally, activated SMAD2/3, increased SOX4, and depressed miRNA-506-3p were associated with SRSF6 upregulation in PMCs. These observations support a model in which SRSF6 induces pleural
fibrosis through a cluster pathway, including SRSF6/WNT5A and SRSF6/SMAD1/5/9 signaling. In conclusion, we propose inhibition of the
splicing factor SRSF6 as a strategy for treatment of pleural
fibrosis.