Sleep regulates hepatic neutrophil trafficking by modulating uric acid metabolism via sympathetic nervous system activity

Abstract

Sleep is essential for survival and serves as a key regulator of metabolic and immune function. Sleep loss is strongly associated with metabolic stress and liver inflammation. The mechanisms linking sleep disruption to hepatic metabolic inflammation (metaflammation) remain poorly defined. Here, we show that sleep loss triggers metaflammation through a sympathetic-metabolic-immune axis. Acute sleep deprivation (SD) activates hepatic sympathetic signaling, leading to increased uric acid (UA) synthesis driven by enhanced expression and activity of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in the liver. Elevated UA, acting as an immune-stimulatory metabolic signal, promotes hepatic neutrophil recruitment and pro-inflammatory cytokine production, a response that is rapidly reversed upon sleep recovery. Our findings identify sleep-dependent sympathetic control of hepatic UA metabolism as a driver of acute liver inflammation and reveal how acute sleep loss reprograms liver immune-metabolic homeostasis.