Oxytocin alleviates liver fibrosis via hepatic macrophages
Xiangyu Zhai,
Hao Zhang,
Zhijia Xia,
Mingkun Liu,
Gang Du,
Zhengchen Jiang,
Huaxin Zhou,
Dan Luo,
Dandan Dou,
Jingxin Li,
Wei Wang,
Xiaosong Li,
Bin Jin
Affiliations
Xiangyu Zhai
Department of Hepatobiliary Surgery, The Second Hospital of Shangdong University, Jinan, China; Hepatobiliary Surgery Research Center of Shandong University, Jinan, China
Hao Zhang
Department of Hepatobiliary Surgery, The Second Hospital of Shangdong University, Jinan, China; Hepatobiliary Surgery Research Center of Shandong University, Jinan, China
Zhijia Xia
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
Mingkun Liu
Organ Transplant Department, Qilu Hospital of Shangdong University, Jinan, China
Gang Du
Hepatobiliary Surgery Research Center of Shandong University, Jinan, China; Organ Transplant Department, Qilu Hospital of Shangdong University, Jinan, China
Zhengchen Jiang
Hepatobiliary Surgery Research Center of Shandong University, Jinan, China; Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
Huaxin Zhou
Department of Hepatobiliary Surgery, The Second Hospital of Shangdong University, Jinan, China; Hepatobiliary Surgery Research Center of Shandong University, Jinan, China
Dan Luo
Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, China
Dandan Dou
Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
Jingxin Li
Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
Wei Wang
Medical Integration and Practice Center, Shandong University, Jinan, China; Corresponding authors. Addresses: Medical Integration and Practice Center, Shandong University, Jinan 250012, China (W. Wang); Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China (X. Li); Department of Hepatobiliary Surgery, The Second Hospital of Shangdong University, Beiyuan Road No. 247, Jinan 250033, China. Tel.: +86-15098772066 (B. Jin).
Xiaosong Li
Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Corresponding authors. Addresses: Medical Integration and Practice Center, Shandong University, Jinan 250012, China (W. Wang); Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China (X. Li); Department of Hepatobiliary Surgery, The Second Hospital of Shangdong University, Beiyuan Road No. 247, Jinan 250033, China. Tel.: +86-15098772066 (B. Jin).
Bin Jin
Department of Hepatobiliary Surgery, The Second Hospital of Shangdong University, Jinan, China; Hepatobiliary Surgery Research Center of Shandong University, Jinan, China; Organ Transplant Department, Qilu Hospital of Shangdong University, Jinan, China; Corresponding authors. Addresses: Medical Integration and Practice Center, Shandong University, Jinan 250012, China (W. Wang); Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China (X. Li); Department of Hepatobiliary Surgery, The Second Hospital of Shangdong University, Beiyuan Road No. 247, Jinan 250033, China. Tel.: +86-15098772066 (B. Jin).
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 Ly6high to Ly6Clow 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 oxytocin-mediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6high to Ly6Clow 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.
