Life sciences · 2025
FOSL2+ macrophages drive pro-inflammatory phenotype via miR-92a-3p/FOSL2/NF-κB axis to mediate endothelial cell injury in aortic dissection.
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Yuan Zhenpeng, Chen Ruihan, Fan Rong, Yang Zhenyu, Zhu Qianqian, Qiu Chenyang, Wu Ziheng, Li Donglin, He Yangyan, Zhang Hongkun
Аннотация
BACKGROUND: In aortic dissection, macrophages play a critical role; however, the impact of macrophages on vascular endothelial cells remains unclear.
METHODS: By constructing macrophage cell lines with stable overexpression and knockdown of FOSL2, M1 polarization was induced to evaluate the effects of FOSL2 on macrophage polarization, pro-inflammatory cytokine expression, macrophage migration, apoptosis, reactive oxygen species (ROS) generation, and mitochondrial function. Additionally, co-culture experiments were conducted to study the effects of macrophages with FOSL2 overexpression and knockdown on the proliferation, migration, apoptosis, and signaling pathways of mouse aortic endothelial cells (MAECs). Furthermore, miRNA prediction and validation experiments were performed to explore the regulatory mechanism of miR-92a-3p on FOSL2 and its role in macrophage-endothelial cell interactions.
RESULTS: Overexpression of FOSL2 enhanced the expression and secretion of pro-inflammatory cytokines, promoting the M1 phenotype. It also increased macrophage migration, apoptosis, and ROS generation while suppressing mitochondrial membrane potential and activating the MYD88/TLR4/NF-κB signaling pathway. In co-culture experiments, FOSL2 overexpression in macrophages inhibited the proliferation and migration of co-cultured MAECs, promoted apoptosis and mitochondrial dysfunction, and upregulated endothelial injury markers and the PI3K/AKT/NF-κB signaling pathway. miR-92a-3p was downregulated during M1 polarization and directly targeted FOSL2, inhibiting its expression. Overexpression of miR-92a-3p reversed the FOSL2-mediated M1 polarization of macrophages and the functional impairment of co-cultured endothelial cells.
CONCLUSION: FOSL2 promotes macrophage M1 polarization by regulating the MYD88/TLR4/NF-κB signaling pathway, enhancing pro-inflammatory responses, and inhibiting the function of co-cultured endothelial cells. miR-92a-3p exerts the opposite effect by targeting FOSL2, suppressing M1 polarization and endothelial cell injury.
METHODS: By constructing macrophage cell lines with stable overexpression and knockdown of FOSL2, M1 polarization was induced to evaluate the effects of FOSL2 on macrophage polarization, pro-inflammatory cytokine expression, macrophage migration, apoptosis, reactive oxygen species (ROS) generation, and mitochondrial function. Additionally, co-culture experiments were conducted to study the effects of macrophages with FOSL2 overexpression and knockdown on the proliferation, migration, apoptosis, and signaling pathways of mouse aortic endothelial cells (MAECs). Furthermore, miRNA prediction and validation experiments were performed to explore the regulatory mechanism of miR-92a-3p on FOSL2 and its role in macrophage-endothelial cell interactions.
RESULTS: Overexpression of FOSL2 enhanced the expression and secretion of pro-inflammatory cytokines, promoting the M1 phenotype. It also increased macrophage migration, apoptosis, and ROS generation while suppressing mitochondrial membrane potential and activating the MYD88/TLR4/NF-κB signaling pathway. In co-culture experiments, FOSL2 overexpression in macrophages inhibited the proliferation and migration of co-cultured MAECs, promoted apoptosis and mitochondrial dysfunction, and upregulated endothelial injury markers and the PI3K/AKT/NF-κB signaling pathway. miR-92a-3p was downregulated during M1 polarization and directly targeted FOSL2, inhibiting its expression. Overexpression of miR-92a-3p reversed the FOSL2-mediated M1 polarization of macrophages and the functional impairment of co-cultured endothelial cells.
CONCLUSION: FOSL2 promotes macrophage M1 polarization by regulating the MYD88/TLR4/NF-κB signaling pathway, enhancing pro-inflammatory responses, and inhibiting the function of co-cultured endothelial cells. miR-92a-3p exerts the opposite effect by targeting FOSL2, suppressing M1 polarization and endothelial cell injury.