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Quercetin-driven M2 polarization of macrophages via ALOX5 inhibition in kupffer cells: A strategy for mouse liver fibrosis treatment.
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Chen Chen, Cui Dejun, Yang Shengpeng, Yuan Wenqiang, Yang Liuchan
Аннотация
BACKGROUND: Liver fibrosis, a key feature of chronic liver diseases, involves dysregulated extracellular matrix accumulation, and whether quercetin alleviates fibrosis by targeting 5-lipoxygenase (ALOX5) in Kupffer cells to modulate macrophage polarization remains unclear.
METHODS: Using a dimethylnitrosamine (DMN)-induced liver fibrosis mouse model, mice were treated with quercetin (20, 50, 80 mg/kg/day) or controls. Hepatic fibrosis was evaluated via histopathology (HE/Masson staining), serum liver function markers (ALT, AST, TBIL), and Suzuki scoring. Kupffer cells and macrophages were isolated for flow cytometry, co-culture assays, and molecular analyses (RT-qPCR, Western blot). ALOX5 expression was manipulated using shRNA lentivirus or overexpression vectors to validate its role in quercetin's mechanism.
RESULTS: Quercetin dose-dependently reduced hepatic inflammatory cell infiltration, collagen deposition, and liver function injury (p < 0.01 or p < 0.001). Mechanistically, quercetin suppressed ALOX5 expression predominantly in Kupffer cells, promoting macrophage polarization from pro-inflammatory M1 (iNOS+) to anti-inflammatory M2 (CD206+) phenotypes (p < 0.01 or p < 0.001). Co-culture experiments showed ALOX5 knockdown in Kupffer cells mimicked the polarization effects of quercetin (p < 0.001), while ALOX5 overexpression promoted M1 polarization (p < 0.001). In vivo, quercetin did not show further antifibrotic benefit when ALOX5 was silenced (p > 0.05), suggesting that ALOX5 is involved in its antifibrotic mechanism.
CONCLUSIONS: Quercetin alleviates liver fibrosis by targeting ALOX5 in Kupffer cells to promote M2 macrophage polarization. These findings suggest that ALOX5 may represent a potential therapeutic target and supports the clinical application of quercetin.
METHODS: Using a dimethylnitrosamine (DMN)-induced liver fibrosis mouse model, mice were treated with quercetin (20, 50, 80 mg/kg/day) or controls. Hepatic fibrosis was evaluated via histopathology (HE/Masson staining), serum liver function markers (ALT, AST, TBIL), and Suzuki scoring. Kupffer cells and macrophages were isolated for flow cytometry, co-culture assays, and molecular analyses (RT-qPCR, Western blot). ALOX5 expression was manipulated using shRNA lentivirus or overexpression vectors to validate its role in quercetin's mechanism.
RESULTS: Quercetin dose-dependently reduced hepatic inflammatory cell infiltration, collagen deposition, and liver function injury (p < 0.01 or p < 0.001). Mechanistically, quercetin suppressed ALOX5 expression predominantly in Kupffer cells, promoting macrophage polarization from pro-inflammatory M1 (iNOS+) to anti-inflammatory M2 (CD206+) phenotypes (p < 0.01 or p < 0.001). Co-culture experiments showed ALOX5 knockdown in Kupffer cells mimicked the polarization effects of quercetin (p < 0.001), while ALOX5 overexpression promoted M1 polarization (p < 0.001). In vivo, quercetin did not show further antifibrotic benefit when ALOX5 was silenced (p > 0.05), suggesting that ALOX5 is involved in its antifibrotic mechanism.
CONCLUSIONS: Quercetin alleviates liver fibrosis by targeting ALOX5 in Kupffer cells to promote M2 macrophage polarization. These findings suggest that ALOX5 may represent a potential therapeutic target and supports the clinical application of quercetin.