Depletion of Kupffer Cells Attenuates APAP-induced Liver Injury
Objective:To explore the role of Kupffer cells in APAP-induced liver injury by using the Cre/iDTR system to specifically deplete Kupffer cells.Methods:Clec4fCre/iDrR mice were injected intraperitoneally with 1 μg DT(Diphtheria Ttoxin,diphtheria toxin),and the depletion efficiency of Kupffer cells in the liver was detected by flow cytometry.Then,Clec4fCre/iDTR mice were divided into four groups,namely control group,DT group,APAP group,DT and APAP group.300 mg/kg APAP was injected intraperitoneally after 18 h of starvation to establish an acute liver injury model.ELISA and CBA analysis were used to detect the release of ALT and AST and the secretion of inflammatory factors in serum.H&E staining and TUNEL staining were used to detect the necrosis of liver tissue and the apoptosis of hepatocytes.Immunohistochemistry was used to detect inflammatory cell infiltration in the liver and immunoblotting to detect activation of the JNK signaling pathway.qPCR was used to detect the transcriptional expression of inflammatory factors in the liver.Results:Hepatic Kupffer cells in Clec4f Cre/iDTR mice were almost completely depleted at 12 and 24 h after injection of 1 µg DT.Depletion of Kupffer cells potently ameliorated APAP-induced liver injury,as manifested by decreased serum ALT and AST levels,less hepatic necrotic area and hepatocyte apoptosis,reduced inflammatory cell infiltration and production of inflammatory cytokines,and abrogated activation of the JNK pathway.Conclusion:This study demonstrated that removal of Kupffer cells significantly attenuated APAP-induced liver injury,suggesting an essential contribution of Kupffer cells to APAP hepatotoxicity.
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