Splicing factor SRSF6 mediates pleural fibrosis
Splicing factor SRSF6 mediates pleural fibrosis
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剪接因子SRSF6介导胸膜纤维化
DOI：
10.1172/jci.insight.146197
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Ma Wan-Li
中科院分区：
文献类型：
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作者：
Liang Li-Mei;Xiong Liang;Cheng Pei-Pei;Chen Shuai-Jun;Feng Xiao;Zhou Ya-Ya;Niu Qian;Wang Meng;Chen Qianlan;Song Lin-Jie;Yu Fan;He Xin-Liang;Xiang Fei;Wang Xiaorong;Ye Hong;Ma Wan-Li
胸膜纤维化定义为细胞外基质过度沉积，导致正常胸膜组织结构破坏和功能受损。结核性胸膜炎、石棉损伤、类风湿性胸膜炎是胸膜纤维化的主要病因。胸膜间皮细胞（PMCs）在胸膜纤维化中起关键作用。然而，详细的机制知之甚少。富含丝氨酸/丝氨酸的蛋白SRSF 6属于高度保守的RNA结合剪接因子蛋白家族。基于其已知的功能，SRSF 6应该被期望在纤维化疾病中发挥作用。然而，SRSF 6在胸膜纤维化中的作用仍然未知。在这项研究中，发现SRSF 6蛋白在患者的结核性胸腔积液（TBPE）细胞中增加，脱细胞TBPE、博莱霉素和TGF-β1被证实可增加PMC中的SRSF 6水平。在体外，SRSF 6介导PMC增殖和主要纤维化蛋白COL 1A 2的合成。在体内，SRSF 6抑制防止小鼠实验性胸膜纤维化。最后，SMAD 2/3激活、SOX 4增加和miRNA-506- 3 p抑制与PMC中SRSF 6上调相关。这些观察结果支持了SRSF 6通过簇通路（包括SRSF 6/WNT 5A和SRSF 6/SMAD 1/5/9信号传导）诱导胸膜纤维化的模型。总之，我们建议抑制剪接因子SRSF 6作为治疗胸膜纤维化的策略。
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.