The HMGB1/RAGE axis triggers neutrophil mediated injury amplification following necrosis.
In contrast to microbially triggered inflammation, mechanisms promoting sterile inflammation remain poorly understood. Damage associated molecular patterns (DAMPs) are considered key inducers of sterile inflammation following cell death, but the relative contribution of specific DAMPs, including high mobility group box 1 (HMGB1) is ill defined. Due to the postnatal lethality of Hmgb1 knockout mice, the role of HMGB1 in sterile inflammation and disease processes in vivo remains controversial. Here, using conditional ablation strategies, we have demonstrated that epithelial, but not bone marrow derived, HMGB1 is required for sterile inflammation following injury. Epithelial HMGB1, through its receptor RAGE, triggered recruitment of neutrophils, but not macrophages, toward necrosis. In clinically relevant models of necrosis, HMGB1/RAGE induced neutrophil recruitment mediated subsequent amplification of injury, depending on the presence of neutrophil elastase. Notably, hepatocyte specific HMGB1 ablation resulted in 100% survival following lethal acetaminophen intoxication. In contrast to necrosis, HMGB1 ablation did not alter inflammation or mortality in response to TNFor FAS mediated apoptosis. In LPS induced shock, in which HMGB1 Research Article Immunology
The Journal of clinical investigation