Oxytocin alleviates liver fibrosis via hepatic macrophages

IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
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
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引用次数: 0

Abstract

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.

Abstract Image

催产素通过肝巨噬细胞缓解肝纤维化
背景& 目的先前的研究表明催产素治疗能有效降低小鼠死亡率并逆转肝纤维化。然而,由于肝星状细胞--主要的肝纤维化效应细胞--缺乏催产素受体表达,其基本机制仍不清楚。方法利用单细胞测序生成了纤维化肝脏中细胞群的综合图谱。该图谱使我们能够从更多维度研究催产素在肝脏中的作用靶细胞。此外,我们还利用催产素受体特异性敲除小鼠和肝纤维化动物模型,阐明了催产素信号系统在肝巨噬细胞中的作用机制。肝细胞群图谱显示,催产素可促进髓源性巨噬细胞的表型从 Ly6high 向 Ly6Clow 转换。利用髓系特异性催产素受体基因敲除小鼠验证了催产素信号系统激活对这种表型转换的表型控制。随后的研究表明,催产素受体激活诱导的钙离子内流激活了关键的孤儿核受体NR4A1,而NR4A1控制着巨噬细胞的表型转换。结论研究结果表明,肝巨噬细胞是催产素介导的肝纤维化缓解的枢纽。本研究揭示了催产素调节巨噬细胞表型的新途径。影响和意义之前的研究首次揭示了催产素受体在肝脏中的表达。本研究表明,催产素能逆转肝纤维化,而肝巨噬细胞是催产素介导的缓解肝纤维化的中心枢纽,它能促进肝巨噬细胞的表型转换,从 Ly6high 表达过渡到 Ly6Clow 表达。本研究揭示了催产素调节巨噬细胞表型的新途径。此外,催产素及其类似物作为临床应用的传统药物,在治疗肝纤维化方面的潜在应用值得进一步探讨。
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来源期刊
JHEP Reports
JHEP Reports GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
12.40
自引率
2.40%
发文量
161
审稿时长
36 days
期刊介绍: JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology. The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies. In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.
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