Mitochondrial folate pathway regulates myofibroblast differentiation and silica-induced pulmonary fibrosis.
Mitochondrial folate pathway regulates myofibroblast differentiation and silica-induced pulmonary fibrosis.
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DOI：
10.1186/s12967-023-04241-0
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发表时间：
2023-06-06
影响因子：
7.4
通讯作者：
Yao, Wu
中科院分区：
文献类型：
--
作者：
Qu, Yaqian;Zhai, Ruonan;Wang, Dandan;Wang, Zheng;Hou, Guangjie;Wu, Chenchen;Tang, Meian;Xiao, Xiongbin;Jiao, Jie;Ba, Yue;Zhou, Fang;Qiu, Jian;Yao, Wu
矽尘肺纤维化（Silica-induced pulmonary fibrosis，silicosis）是一种弥漫性间质纤维化疾病，其特征是肺组织中细胞外基质大量沉积。成纤维细胞向成肌纤维细胞的分化对于疾病进展至关重要。抑制肌成纤维细胞分化可能是治疗肺纤维化的有效途径。在TGF-β处理的人肺成纤维细胞中进行实验以在体外诱导肌成纤维细胞分化，并且在二氧化硅处理的小鼠中进行实验以在体内诱导肺纤维化。通过定量质谱，我们揭示了参与线粒体叶酸代谢的蛋白质在TGF-β刺激后的肌成纤维细胞分化期间特异性上调。线粒体叶酸途径中的蛋白质MTHFD 2和SLC 25 A32的表达水平负调控肌成纤维细胞分化。此外，矽肺患者和小鼠的血浆叶酸浓度显著降低。补充叶酸可提高MTHFD 2和SLC 25 A32的表达，减轻氧化应激，有效抑制小鼠成肌纤维细胞分化和二氧化硅诱导的肺纤维化。我们的研究表明，线粒体叶酸途径调节肌成纤维细胞的分化，并可能作为一个潜在的目标，改善二氧化硅诱导的肺纤维化。在线版本包含补充材料，可通过10.1186/s12967-023-04241-0获得。
Silica-induced pulmonary fibrosis (silicosis) is a diffuse interstitial fibrotic disease characterized by the massive deposition of extracellular matrix in lung tissue. Fibroblast to myofibroblast differentiation is crucial for the disease progression. Inhibiting myofibroblast differentiation may be an effective way for pulmonary fibrosis treatment. The experiments were conducted in TGF-β treated human lung fibroblasts to induce myofibroblast differentiation in vitro and silica treated mice to induce pulmonary fibrosis in vivo. By quantitative mass spectrometry, we revealed that proteins involved in mitochondrial folate metabolism were specifically upregulated during myofibroblast differentiation following TGF-β stimulation. The expression level of proteins in mitochondrial folate pathway, MTHFD2 and SLC25A32, negatively regulated myofibroblast differentiation. Moreover, plasma folate concentration was significantly reduced in patients and mice with silicosis. Folate supplementation elevated the expression of MTHFD2 and SLC25A32, alleviated oxidative stress and effectively suppressed myofibroblast differentiation and silica-induced pulmonary fibrosis in mice. Our study suggests that mitochondrial folate pathway regulates myofibroblast differentiation and could serve as a potential target for ameliorating silica-induced pulmonary fibrosis. The online version contains supplementary material available at 10.1186/s12967-023-04241-0.
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