Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation

The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival.