Splicing factor SRSF6 mediates pleural fibrosis

Our plain-English summary of Splicing factor SRSF6 mediates pleural fibrosis, by L.M. Liang, L. Xiong, P.P. Cheng, et al (JCI Insight, 2021).

The study

• Authors: L.M. Liang, L. Xiong, P.P. Cheng, S.J. Chen, X. Feng, Y.Y. Zhou, Q. Niu, M. Wang, Q. Chen, L.J. Song, F. Yu, X.L. He, F. Xiang, X. Wang, H. Ye, W.L. Ma
• Journal: JCI Insight
• Published: 2021;6(10)
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study looked at a protein called SRSF6 in pleural fibrosis, the scarring and thickening of the lining around the lungs. The introduction lists asbestos injury as one cause of pleural fibrosis, but the study did not test asbestos. It used pleural fluid from tuberculosis patients, the drug bleomycin, and the growth factor TGF-β1. SRSF6 was higher in cells from tuberculous pleural effusions (8 patients) than in cells from transudative effusions (4 patients). In cultured pleural lining cells, tuberculous fluid, bleomycin and TGF-β1 each raised SRSF6. When SRSF6 was reduced, these triggers no longer drove the cells to multiply. In mice given bleomycin plus carbon particles into the chest, reducing SRSF6 lessened pleural fibrosis. The authors also traced signals upstream and downstream of SRSF6, involving SMAD2/3, SOX4, miR-506-3p, WNT5A and SMAD5. They concluded that SRSF6 is a key mediator in pleural fibrosis and proposed blocking it as a treatment strategy. The authors did not state limitations.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining patient pleural fluid samples, cultured cells (a human pleural mesothelial cell line and rat primary pleural cells) and a mouse model of pleural fibrosis
• Who was studied: Cells from pleural fluid of patients at Union Hospital, Wuhan, China: tuberculous pleural effusion (n = 8) and transudative pleural effusion (n = 4). Also the human pleural mesothelial cell line Met-5A, rat primary pleural mesothelial cells, and male C57BL/6J mice aged 6 to 8 weeks. Mouse groups: n = 7 (control shRNA), n = 8 (control shRNA plus bleomycin and carbon), n = 6 (SRSF6 shRNA3) and n = 6 (SRSF6 shRNA3 plus bleomycin and carbon). Collection dates are not given.
• Exposure: No asbestos was studied. Cultured cells were treated with cell-free tuberculous pleural effusion (5%), bleomycin (0.2 μg/mL) or TGF-β1 (5 ng/mL). Mice received a single injection into the chest cavity of bleomycin (0.48 μg per mouse) plus carbon particles (0.1 mg per mouse). They were then given lentivirus carrying SRSF6 shRNA or a control shRNA on days 4, 7 and 10.
• Main results:
  • SRSF6 protein and mRNA were significantly higher in cells from tuberculous pleural effusions than in cells from transudative pleural effusions.
  • In cultured human pleural mesothelial cells, tuberculous effusion raised SRSF6 at 24 or 48 hours. The rise in SRSF6 and COL1A2 protein caused by TGF-β1 depended on dose.
  • An SRSF6 siRNA that lowered SRSF6 protein by about 70% stopped the cells from multiplying in response to tuberculous effusion, bleomycin or TGF-β1. It also prevented the rise in the fibrosis-related proteins COL1A2 and ACTA2.
  • In mice given bleomycin plus carbon particles, pleural thickening and fibrosis developed. Lentivirus carrying SRSF6 shRNA, given into the chest cavity, lessened the fibrosis.
  • miR-506-3p, a small RNA that lowered SRSF6, was reduced in exosomes (small particles released by cells) from tuberculous effusion compared with transudative effusion. It was also suppressed in cells treated with tuberculous effusion, bleomycin or TGF-β1.
  • In bleomycin-treated cells, RNA sequencing (based on 2 samples) found 684 genes whose activity changed when SRSF6 was reduced: 331 went up and 353 went down.
  • Bleomycin and TGF-β1 increased WNT5A in pleural mesothelial cells, and SRSF6 siRNA inhibited WNT5A expression.
• The authors' conclusion: The authors concluded that SRSF6 is a key mediator in pleural fibrosis. They proposed inhibiting SRSF6 as a strategy for treating pleural fibrosis.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Fibrosis, Deposition, Tuberculous pleurisy, Pleurisy, Mesothelial Cells, Pleural Effusion.

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