PGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis
Abstract Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage–myofibroblast t...
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| Format: | Article |
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Nature Publishing Group
2025-04-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01426-z |
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| author | Yawen Peng Shuya Mei Xiaohui Qi Ri Tang Wenyu Yang Jinhua Feng Yang Zhou Xi Huang Guojun Qian Shunpeng Xing Yuan Gao Qiaoyi Xu Zhengyu He |
| author_facet | Yawen Peng Shuya Mei Xiaohui Qi Ri Tang Wenyu Yang Jinhua Feng Yang Zhou Xi Huang Guojun Qian Shunpeng Xing Yuan Gao Qiaoyi Xu Zhengyu He |
| author_sort | Yawen Peng |
| collection | DOAJ |
| description | Abstract Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage–myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF. |
| format | Article |
| id | doaj-art-72ea7e20dabb481894f7215e09b272b6 |
| institution | DOAJ |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-72ea7e20dabb481894f7215e09b272b62025-08-20T02:55:31ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-04-0157475977410.1038/s12276-025-01426-zPGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosisYawen Peng0Shuya Mei1Xiaohui Qi2Ri Tang3Wenyu Yang4Jinhua Feng5Yang Zhou6Xi Huang7Guojun Qian8Shunpeng Xing9Yuan Gao10Qiaoyi Xu11Zhengyu He12Department of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiovascular Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineKey Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of EducationDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Critical Care Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineAbstract Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage–myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF.https://doi.org/10.1038/s12276-025-01426-z |
| spellingShingle | Yawen Peng Shuya Mei Xiaohui Qi Ri Tang Wenyu Yang Jinhua Feng Yang Zhou Xi Huang Guojun Qian Shunpeng Xing Yuan Gao Qiaoyi Xu Zhengyu He PGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis Experimental and Molecular Medicine |
| title | PGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis |
| title_full | PGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis |
| title_fullStr | PGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis |
| title_full_unstemmed | PGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis |
| title_short | PGC-1α mediates migrasome secretion accelerating macrophage–myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis |
| title_sort | pgc 1α mediates migrasome secretion accelerating macrophage myofibroblast transition and contributing to sepsis associated pulmonary fibrosis |
| url | https://doi.org/10.1038/s12276-025-01426-z |
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