Background and Aims:We previously reported that carboxylesterase 1(CES1)expression was suppressed following liver injury.The study aimed to explore the role of interleukin(IL)-33 in liver injury and examine the mechan...Background and Aims:We previously reported that carboxylesterase 1(CES1)expression was suppressed following liver injury.The study aimed to explore the role of interleukin(IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1.Methods:IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide(LPS)-,acetaminophen(APAP)-treated mice.We constructed IL-33 and ST2 knockout(KO)mice.ST2-enriched immune cells in livers were screened to identify the responsible cells.Macrophage-derived exosome(MDE)activity was tested by adding exosome inhibitors.Micro-RNAs(miRs)were extracted from control and IL-33-stimulated MDEs(IL-33-MDEs)and subjected miR sequencing(miR-Seq).Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays.Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p.Results:Patient liver IL-33 and CES1 expression levels were inversely correlated.CES1 downregulation in liver injury was rescued in both IL-33–deficient and ST2 KO mice.Macrophages were shown to be responsible for IL-33 effects.IL-33-MDEs reduced CES1 levels in hepatocytes.Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs;miR-27b-3p was implicated in Nrf2 targeting.IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent.Conclusions:IL-33–ST2–GATA3 pathway signaling increases miR-27b-3p content in MDEs,which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2.The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.展开更多
基金supported by the National Natural Science Foundation of China(81670521 and 81803798).
文摘Background and Aims:We previously reported that carboxylesterase 1(CES1)expression was suppressed following liver injury.The study aimed to explore the role of interleukin(IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1.Methods:IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide(LPS)-,acetaminophen(APAP)-treated mice.We constructed IL-33 and ST2 knockout(KO)mice.ST2-enriched immune cells in livers were screened to identify the responsible cells.Macrophage-derived exosome(MDE)activity was tested by adding exosome inhibitors.Micro-RNAs(miRs)were extracted from control and IL-33-stimulated MDEs(IL-33-MDEs)and subjected miR sequencing(miR-Seq).Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays.Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p.Results:Patient liver IL-33 and CES1 expression levels were inversely correlated.CES1 downregulation in liver injury was rescued in both IL-33–deficient and ST2 KO mice.Macrophages were shown to be responsible for IL-33 effects.IL-33-MDEs reduced CES1 levels in hepatocytes.Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs;miR-27b-3p was implicated in Nrf2 targeting.IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent.Conclusions:IL-33–ST2–GATA3 pathway signaling increases miR-27b-3p content in MDEs,which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2.The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.
