International immunopharmacology · 2025
hnRNPA2B1 promotes the production of exosomal miR-103-3p from endothelial progenitor cells to alleviate macrophage M1 polarization in acute respiratory distress syndrome.
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Yang Lei, Chen Ting, Huang Yuanlu, Yang Yuxuan, Cheng Xiaoe, Wei Fusheng
Аннотация
BACKGROUND: Macrophage polarization plays a crucial role in acute respiratory distress syndrome (ARDS). Recently, mounting evidence has uncovered that endothelial progenitor cells (EPCs) secreted exosomes (EPCs-Exos) exert obvious therapeutic effects on the pathological inflammatory process of ARDS, but its potential mechanism is rarely reported.
METHODS: The primary mouse EPCs and EPCs-Exos were isolated and identified. Absorption of EPCs-Exos by RAW264.7 cells was examined by PKH-26 staining. The polarization of RAW264.7 cells was evaluated by flow cytometry and RT-qPCR analysis. Molecular interactions were verified by dual luciferase assay, RNA pull-down and RNA immunocoprecipitation assays. ARDS mouse model was established, and pathological changes and expressions of related molecules were detected by HE staining, RT-qPCR and western blotting.
RESULTS: EPCs-Exos could be transferred to macrophages, and effectively reversed LPS-induced polarization of macrophages from M2 to M1 phenotype; however, these changes were diminished by activation of TLR4/NF-κB pathway. MiR-103-3p was proved to be enriched in EPC-Exos and could transfer to macrophage and inactivating TLR4/NF-κB pathway via directly binding to TLR4 3'-UTR. Moreover, miR-103-3p overexpression elevated macrophage M2 polarization and repressed M1 polarization in LPS-treated cells by inhibiting TLR4/NF-κB pathway, and knockdown of miR-103-3p in EPC-Exos abolished the regulatory roles of EPC-Exos on macrophage polarization in vitro, and lung inflammatory injury in vivo. HnRNPA2B1 was proved to interact with miR-103-3p and responsible for its exosomal secretion, which repressed pro-inflammatory macrophage polarization.
CONCLUSION: These findings suggested that hnRNPA2B1-mediated exosomal delivery of miR-103-3p from EPCs protected against macrophage inflammation in ARDS by inactivation of TLR4/NF-κB pathway.
METHODS: The primary mouse EPCs and EPCs-Exos were isolated and identified. Absorption of EPCs-Exos by RAW264.7 cells was examined by PKH-26 staining. The polarization of RAW264.7 cells was evaluated by flow cytometry and RT-qPCR analysis. Molecular interactions were verified by dual luciferase assay, RNA pull-down and RNA immunocoprecipitation assays. ARDS mouse model was established, and pathological changes and expressions of related molecules were detected by HE staining, RT-qPCR and western blotting.
RESULTS: EPCs-Exos could be transferred to macrophages, and effectively reversed LPS-induced polarization of macrophages from M2 to M1 phenotype; however, these changes were diminished by activation of TLR4/NF-κB pathway. MiR-103-3p was proved to be enriched in EPC-Exos and could transfer to macrophage and inactivating TLR4/NF-κB pathway via directly binding to TLR4 3'-UTR. Moreover, miR-103-3p overexpression elevated macrophage M2 polarization and repressed M1 polarization in LPS-treated cells by inhibiting TLR4/NF-κB pathway, and knockdown of miR-103-3p in EPC-Exos abolished the regulatory roles of EPC-Exos on macrophage polarization in vitro, and lung inflammatory injury in vivo. HnRNPA2B1 was proved to interact with miR-103-3p and responsible for its exosomal secretion, which repressed pro-inflammatory macrophage polarization.
CONCLUSION: These findings suggested that hnRNPA2B1-mediated exosomal delivery of miR-103-3p from EPCs protected against macrophage inflammation in ARDS by inactivation of TLR4/NF-κB pathway.