Oxytocin alleviates liver fibrosis via hepatic macrophages

作者：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 · 发表于：JHEP Reports · 年份：2024 · DOI：10.1016/j.jhepr.2024.101032 · 被引用次数：56 · 研究领域：Neuroendocrine regulation and behavior、Liver physiology and pathology、Reproductive System and Pregnancy

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: 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: expression. The present study reveals a novel pathway by which oxytocin...