Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury
Abstract Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe complication of sepsis and the leading cause of mortality. Although the role of alveolar macrophages (AMs) in stabilizing pulmonary homeostasis is well established, the effects of circulating extracellular vesicles (EVs)...
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BMC
2025-02-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01111-x |
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| author | Rongzong Ye Yating Wei Jingwen Li Yu Zhong Xiukai Chen Chaoqian Li |
| author_facet | Rongzong Ye Yating Wei Jingwen Li Yu Zhong Xiukai Chen Chaoqian Li |
| author_sort | Rongzong Ye |
| collection | DOAJ |
| description | Abstract Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe complication of sepsis and the leading cause of mortality. Although the role of alveolar macrophages (AMs) in stabilizing pulmonary homeostasis is well established, the effects of circulating extracellular vesicles (EVs) on AMs remain largely unknown. In this study, an investigation was conducted to map the miRNA and protein expression profiles of EVs derived from septic plasma. Notably, EV-based panels (miR-122-5p, miR-125b-5p, miR-223-3p, OLFM4, and LCN2) have been found to be associated with the severity or prognosis of sepsis, with promising AUC values. Moreover, the levels of LCN2, miR-122-5p, and miR-223-3p were identified as independent predictors of septic ARDS. The in vitro coculture results revealed that the effects of LPS-EVs from the plasma of sepsis-induced acute lung injury (ALI), which carry pro-inflammatory EVs, were partly mediated by miR-223-3p, as evidenced by the promotion of inflammation, autophagy and ferroptosis in AMs. Mechanistically, the upregulation of miR-223-3p in LPS-EVs triggers autophagy and ferroptosis in AMs by activating Hippo signaling via the targeting of MEF2C. In vivo, the inhibition of miR-223-3p effectively mitigated LPS-EV-induced inflammation and AM death in the lungs, as well as histological lesions. Overall, miR-223-3p in LPS-EVs contributes to sepsis-induced ALI by priming AMs for autophagy and ferroptosis through the MEF2C/Hippo signaling pathway. These findings suggest a novel mechanism of plasma-AM interaction in sepsis-induced ALI, offering a plausible strategy for assessing septic progression and treating lung injury. |
| format | Article |
| id | doaj-art-3c8155d9de30434a85b011345826b267 |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-3c8155d9de30434a85b011345826b2672025-02-09T12:42:12ZengBMCMolecular Medicine1528-36582025-02-0131112110.1186/s10020-025-01111-xPlasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injuryRongzong Ye0Yating Wei1Jingwen Li2Yu Zhong3Xiukai Chen4Chaoqian Li5Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical UniversityDepartment of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical UniversityGuangxi Medical UniversityDepartment of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical UniversityDepartment of Critical Care Medicine, The First Affiliated Hospital of Xiamen UniversityDepartment of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical UniversityAbstract Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe complication of sepsis and the leading cause of mortality. Although the role of alveolar macrophages (AMs) in stabilizing pulmonary homeostasis is well established, the effects of circulating extracellular vesicles (EVs) on AMs remain largely unknown. In this study, an investigation was conducted to map the miRNA and protein expression profiles of EVs derived from septic plasma. Notably, EV-based panels (miR-122-5p, miR-125b-5p, miR-223-3p, OLFM4, and LCN2) have been found to be associated with the severity or prognosis of sepsis, with promising AUC values. Moreover, the levels of LCN2, miR-122-5p, and miR-223-3p were identified as independent predictors of septic ARDS. The in vitro coculture results revealed that the effects of LPS-EVs from the plasma of sepsis-induced acute lung injury (ALI), which carry pro-inflammatory EVs, were partly mediated by miR-223-3p, as evidenced by the promotion of inflammation, autophagy and ferroptosis in AMs. Mechanistically, the upregulation of miR-223-3p in LPS-EVs triggers autophagy and ferroptosis in AMs by activating Hippo signaling via the targeting of MEF2C. In vivo, the inhibition of miR-223-3p effectively mitigated LPS-EV-induced inflammation and AM death in the lungs, as well as histological lesions. Overall, miR-223-3p in LPS-EVs contributes to sepsis-induced ALI by priming AMs for autophagy and ferroptosis through the MEF2C/Hippo signaling pathway. These findings suggest a novel mechanism of plasma-AM interaction in sepsis-induced ALI, offering a plausible strategy for assessing septic progression and treating lung injury.https://doi.org/10.1186/s10020-025-01111-xExtracellular vesiclesMicroRNAsSepsis-induced acute lung injuryAlveolar macrophagesAutophagyFerroptosis |
| spellingShingle | Rongzong Ye Yating Wei Jingwen Li Yu Zhong Xiukai Chen Chaoqian Li Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury Molecular Medicine Extracellular vesicles MicroRNAs Sepsis-induced acute lung injury Alveolar macrophages Autophagy Ferroptosis |
| title | Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury |
| title_full | Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury |
| title_fullStr | Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury |
| title_full_unstemmed | Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury |
| title_short | Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury |
| title_sort | plasma derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis induced acute lung injury |
| topic | Extracellular vesicles MicroRNAs Sepsis-induced acute lung injury Alveolar macrophages Autophagy Ferroptosis |
| url | https://doi.org/10.1186/s10020-025-01111-x |
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