Oxytocin alleviates liver fibrosis via hepatic macrophages

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 oxytocin signaling system mechanism in hepatic macrophages using oxytocin receptor-specific knockout mice and liver fibrosis animal models. Results The carbon tetrachloride (CCl4)-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 the above phenotypic switch was validated using myeloid-specific OXTR 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. Conclusion 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.