Intervention Mechanism of miR-155 in Macrophage-Derived Exosomes from Sepsis Patients on Endothelial Cell Ferroptosis

Zhijie CHENG; Ruijing ZUO; Huanhuan LI; Linxia WU; Minchen KAN; Qianqian WANG

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Zhijie CHENG, Ruijing ZUO, Huanhuan LI, Linxia WU, Minchen KAN, Qianqian WANG. Intervention Mechanism of miR-155 in Macrophage-Derived Exosomes from Sepsis Patients on Endothelial Cell Ferroptosis[J]. Journal of Kunming Medical University.

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Intervention Mechanism of miR-155 in Macrophage-Derived Exosomes from Sepsis Patients on Endothelial Cell Ferroptosis

Emergency Department II，Handan Central Hospital，Handan Hebei 056000，China

Received Date: 2025-07-22

Abstract

Abstract

Objective To investigate the intervention mechanism of miR-155 in alveolar macrophage （AM）-derived exosomes （Exos） on ferroptosis of endothelial cells in septic patients. Methods This was a single-center study of 106 septic patients admitted to Handan Central Hospital from January 2022 to June 2023. Patients were further stratified into ARDS group （n = 21） and non-ARDS group （n = 85） based on the presence or absence of acute respiratory distress syndrome （ARDS）. In vitro, exosomes from lipopolysaccharide （LPS）-treated Raw 264.7 cells were co-cultured with mouse pulmonary microvascular endothelial cells （PMVEC） as the LPS-Exos group. Exosomes extracted from normal Raw 264.7 culture supernatant served as the normal control group （NC-Exos）, and PMVEC cell culture alone served as the blank control group （Con）. Exosomes were isolated from conditional culture medium of macrophages or bronchoalveolar lavage fluid （BALF） from septic patients. miR-155 expression was analyzed by RT-qPCR, and GPX4 and Nrf2 protein expression was analyzed by Western blotting. Changes in Fe²⁺, SOD and ROS levels in PMVEC cells were detected using assay kits. Results Compared to the non-ARDS group, the ARDS group exhibited higher age, SOFA score, miR-155 expression, and lactate levels （P < 0.05）. miR-155 expression was significantly upregulated in LPS-Exos compared to NC-Exos （P < 0.01）. Compared with Con group, the activity and SOD level of PMVEC cells in LPS-Exos group decreased （P < 0.01）, while the levels of Fe²⁺ and ROS in cells increased （P < 0.05）. Compared with NC-Exos group, the protein expression of classical ferroptosis suppressor genes such as GPX4 and Nrf2 in PMVEC cells was decreased in LPS-Exos group （P < 0.05）. Compared with Con group, PMVEC cell viability, SOD levels, and GPX4 and Nrf2 protein expression were decreased in the Inhibitor-NC+LPS-Exos group （P < 0.001）, while Fe²⁺ and ROS levels were increased （P < 0.0001）. Compared with the Inhibitor-NC+LPS-Exos group, PMVEC cell viability, SOD levels, and GPX4 and Nrf2 protein expression were increased in the miR-155 Inhibitor+LPS-Exos group （P < 0.001）, while Fe²⁺ and ROS levels were decreased （P < 0.01）. Dual-luciferase reporter analysis confirmed direct binding between miR-155 and Nrf2. Conclusion The elevated level of miR-155 in AM-derived Exos has a superior predictive ability for ARDS development in septic patients compared to the SOFA score. When combined with the SOFA score, it demonstrates high predictive capability for ARDS development in septic patients. LPS-induced AM-derived Exos may promote ferroptosis of PMVEC cells by transporting miR-155, and this mechanism may be related to suppression of Nrf2 expression.
- Sepsis,
- Alveolar macrophages,
- Exosome,
- Pulmonary microvascular endothelial cells,
- Ferroptosis,
- miR-155

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