Study summary · research use only
Oxytocin alleviates liver fibrosis via hepatic macrophages
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This mouse study examined how oxytocin was associated with reversal of liver fibrosis via hepatic macrophages, using single-cell sequencing to map liver cell populations and oxytocin receptor-specific knockout mice, in carbon tetrachloride-induced and bile duct ligation liver fibrosis models. Oxytocin was associated with reversal of hepatic fibrosis and with promoting a phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages; this switch was validated using myeloid-specific oxytocin receptor knockout mice. The authors report that calcium influx from oxytocin receptor activation activated the nuclear receptor NR4A1 via CREB, and describe hepatic macrophages as a hub for oxytocin-mediated alleviation of liver fibrosis, describing a previously unreported pathway by which oxytocin regulates macrophage phenotype.
Abstract
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. 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. 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. 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. 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.
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