Oxytocin alleviates liver fibrosis via hepatic macrophages

作者全名：Zhai, Xiangyu; Zhang, Hao; Xia, Zhijia; Liu, Mingkun; Du, Gang; Jiang, Zhengchen; Zhou, Huaxin; Luo, Dan; Dou, Dandan; Li, Jingxin; Wang, Wei; Li, Xiaosong; Jin, Bin

作者地址：[Zhai, Xiangyu; Zhang, Hao; Zhou, Huaxin; Jin, Bin] Shangdong Univ, Hosp 2, Dept Hepatobiliary Surg, Beiyuan Rd 247, Jinan 250033, Peoples R China; [Zhai, Xiangyu; Zhang, Hao; Du, Gang; Jiang, Zhengchen; Zhou, Huaxin; Jin, Bin] Shandong Univ, Hepatobiliary Surg Res Ctr, Jinan, Peoples R China; [Xia, Zhijia] Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany; [Liu, Mingkun; Du, Gang; Jin, Bin] Shangdong Univ, Qilu Hosp, Organ Transplant Dept, Jinan, Peoples R China; [Jiang, Zhengchen] Shandong Univ, Shandong Prov Qianfoshan Hosp, Cheeloo Coll Med, Dept Gen Surg, Jinan, Peoples R China; [Luo, Dan] Shandong Univ, Qilu Hosp, Pathol Tissue Bank, Jinan, Peoples R China; [Dou, Dandan; Li, Jingxin] Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Physiol, Jinan, Peoples R China; [Wang, Wei] Shandong Univ, Med Integrat & Practice Ctr, Jinan 250012, Peoples R China; [Li, Xiaosong] Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing 400016, Peoples R China

通信作者：Jin, B (通讯作者)，Shangdong Univ, Hosp 2, Dept Hepatobiliary Surg, Beiyuan Rd 247, Jinan 250033, Peoples R China.; Wang, W (通讯作者)，Shandong Univ, Med Integrat & Practice Ctr, Jinan 250012, Peoples R China.; Li, XS (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing 400016, Peoples R China.

来源：JHEP REPORTS

ESI学科分类：　

WOS号：WOS:001247654700001

JCR分区：Q1

影响因子：9.5

年份：2024

卷号：6

期号：6

开始页：　

结束页：　

文献类型：Article

关键词：Oxytocin; Liver fibrosis; Hepatic macrophages

摘要：Background & Aims: Previous studies demonstrated oxytocin treatment effectiveness in reducing mortality and reversing liver fibrosis in mice. However, the underlying mechanism remains obscure, given the absence of oxytocin receptor expression in hepatic stellate cells, the primary liver fibrosis effector cells. Methods: A comprehensive map of cell populations in fibrotic liver was generated using single -cell sequencing. The map enabled our study of the target cells of oxytocin action in the liver in more dimensions. Furthermore, we elucidated the mechanism of the oxytocin signaling system in hepatic macrophages using oxytocin receptor -specific knockout mice and liver fibrosis animal models. Results: The carbon tetrachloride -induced hepatic fibrosis and bile duct ligation hepatic fibrosis mouse models demonstrated that oxytocin reversed hepatic fibrosis in mice. The mapped liver cell populations demonstrated that oxytocin promoted the phenotypic switch from Ly6 high to Ly6C low in myeloid -derived macrophages. The phenotypic control of oxytocin signaling system activation on this phenotypic switch was validated using myeloid -specific oxytocin receptor knockout mice. Subsequent studies demonstrated that the calcium inward flow induced by oxytocin receptor activation activated the key orphan nuclear receptor NR4A1, which controls macrophage phenotypic switching. Specifically, calcium ions activated CREB, a key target regulator of NR4A1 expression. Conclusions: The findings established hepatic macrophages as a hub responsible for the oxytocin-mediated alleviation of liver fibrosis. This study revealed a novel pathway where oxytocin regulates macrophage phenotype. Impact and implications: Previous studies revealed for the first time the expression of oxytocin receptors in the liver. The present study shows that oxytocin reverses hepatic fibrosis and that hepatic macrophages are the central hub of oxytocinmediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6 high to Ly6C low expression. The present study reveals a novel pathway by which oxytocin regulates macrophage phenotype. In addition, the potential applications of oxytocin and its analogues, as traditional drugs for clinical application, in the treatment of liver fibrosis deserve to be further explored. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

基金机构：Second Hospital of Shandong University Cultivation Funding [2022YP45]

基金资助正文：Financial support This work was supported by the Second Hospital of Shandong University Cultivation Funding (No. 2022YP45) .