Hepatocyte specific HMGB1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular HMGB1 in cellular protection

High mobility group box-1 (HMGB1) is an abundant chromatin associated nuclear protein and released into the extracellular milieu during liver ischemia/reperfusion (I/R), signaling the activation of pro-inflammatory cascades. Since the intracellular function of HMGB1 during the sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes following liver I/R. When hepatocyte specific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a non-lethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly (ADP-ribose) polymerase-1 (PARP-1) activation, exhausting NAD + and ATP stores, exacerbating mitochondrial instability and damage, and consequently leading to increased cell death. We found that this was also associated with significantly more oxidative stress in HMGB1-HC-KO mice compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through the activation of TLR9.