Immunity, inflammation and disease · 2026
METTL3 Alleviates Liver Abscess by Enhancing Macrophage Efferocytosis via m6A Methylation of Nrf2 mRNA.
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Wang Genwang, Luo Ding, Pang Yu, Gao Chanjuan, Jin Dong, Wang Qi
Аннотация
BACKGROUND: Persistent inflammation and impaired macrophage efferocytosis contribute to liver injury during bacterial liver abscesses (BLA). This study was conducted to investigate whether METTL3 alleviates BLA by promoting macrophage efferocytosis through m6A methylation of Nrf2 mRNA.
MATERIALS AND METHODS: METTL3 was overexpressed in the liver of a Klebsiella pneumoniae-induced BLA mouse model. Liver injury, serum cytokine levels, Nrf2 signaling, m6A enrichment of Nrf2 mRNA, TAM receptor expression, and macrophage-associated Mertk and Nrf2 expression were evaluated. Nrf2 knockdown rescue experiments were further performed in lipopolysaccharide-stimulated RAW264.7 macrophages.
RESULTS: METTL3 overexpression reduced hepatic abscess formation and tissue injury, decreased serum interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) levels, and increased IL-10 and transforming growth factor beta (TGF-β) levels. METTL3 overexpression also enhanced m6A enrichment of Nrf2 mRNA, activated Nrf2/HO-1 signaling, and upregulated the efferocytosis-related receptors MerTK, Tyro3, and AXL in BLA liver tissues. Immunofluorescence analysis revealed increased co-expression of MerTK and Nrf2 in hepatic macrophages. In RAW264.7 cells, Nrf2 knockdown reversed the METTL3-induced upregulation of MerTK, Tyro3, and AXL, as well as the decrease in CD86-positive cells and increase in CD206-positive cells.
CONCLUSIONS: These findings demonstrate that METTL3 promotes m6A methylation of Nrf2 mRNA, activates the Nrf2/TAM receptor axis, enhances macrophage efferocytosis, and alleviates BLA.
MATERIALS AND METHODS: METTL3 was overexpressed in the liver of a Klebsiella pneumoniae-induced BLA mouse model. Liver injury, serum cytokine levels, Nrf2 signaling, m6A enrichment of Nrf2 mRNA, TAM receptor expression, and macrophage-associated Mertk and Nrf2 expression were evaluated. Nrf2 knockdown rescue experiments were further performed in lipopolysaccharide-stimulated RAW264.7 macrophages.
RESULTS: METTL3 overexpression reduced hepatic abscess formation and tissue injury, decreased serum interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) levels, and increased IL-10 and transforming growth factor beta (TGF-β) levels. METTL3 overexpression also enhanced m6A enrichment of Nrf2 mRNA, activated Nrf2/HO-1 signaling, and upregulated the efferocytosis-related receptors MerTK, Tyro3, and AXL in BLA liver tissues. Immunofluorescence analysis revealed increased co-expression of MerTK and Nrf2 in hepatic macrophages. In RAW264.7 cells, Nrf2 knockdown reversed the METTL3-induced upregulation of MerTK, Tyro3, and AXL, as well as the decrease in CD86-positive cells and increase in CD206-positive cells.
CONCLUSIONS: These findings demonstrate that METTL3 promotes m6A methylation of Nrf2 mRNA, activates the Nrf2/TAM receptor axis, enhances macrophage efferocytosis, and alleviates BLA.