单位：[1]Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China[2]Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China华中科技大学同济医学院附属同济医院[3]The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China[4]The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China[5]Wuhan Forth Hospital, Wuhan, Hubei, China
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-27b3p. 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.
基金：
National Natural Science Foundation of China [81670521, 81803798]
第一作者单位：[1]Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
共同第一作者：
通讯作者：
通讯机构：[2]Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China[*1]Tongji Hospital Affiliated with Tongji Medical College,Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
推荐引用方式(GB/T 7714)：
Gao Ping,Li Min,Lu Jingli,et al.IL-33 Downregulates Hepatic Carboxylesterase 1 in Acute Liver Injury via Macrophage-Derived Exosomal miR-27b-3p[J].JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY.2023,11(5):1130-1142.doi:10.14218/JCTH.2022.00144.
APA：
Gao, Ping,Li, Min,Lu, Jingli,Xiang, Daochun,Wang, Ximin...&Zhang, Chengliang.(2023).IL-33 Downregulates Hepatic Carboxylesterase 1 in Acute Liver Injury via Macrophage-Derived Exosomal miR-27b-3p.JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY,11,(5)
MLA：
Gao, Ping,et al."IL-33 Downregulates Hepatic Carboxylesterase 1 in Acute Liver Injury via Macrophage-Derived Exosomal miR-27b-3p".JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY 11..5(2023):1130-1142
