Systemic inflammation and remote organ injury following trauma require HMGB1

Ryan M. Levy, Kevin P. Mollen, Jose M. Prince, David J. Kaczorowski, Raghuveer Vallabhaneni, Shiguang Liu, Kevin J. Tracey, Michael T. Lotze, David J. Hackam, Mitchell P. Fink, Yoram Vodovotz, Timothy R. Billiar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

192 Scopus citations


High-mobility group box 1 (HMGB1) is a 30-kDa DNA-binding protein that displays proinflammatory cytokine-like properties. HMGB1-dependent inflammatory processes have been demonstrated in models of sterile injury, including ischemia-reperfusion injury and hemorrhagic shock. Here, we tested the hypothesis that the systemic inflammatory response and associated remote organ injury that occur after peripheral tissue injury are highly dependent on HMGB1. Toll-like receptor 4 (TLR4) wild-type (WT) mice subjected to bilateral femur fracture after treatment with neutralizing antibodies to HMGB1 had lower serum IL-6 and IL-10 levels compared with mice treated with non-immune control IgG. Similarly, compared with injured mice treated with control IgG, anti-HMGB1 antibody-treated mice had lower serum alanine aminotransferase levels and decreased hepatic and gut mucosal NF-κB DNA binding. TLR4 mutant (C3H/HeJ) mice subjected to bilateral femur fracture had less systemic inflammation and liver injury than WT controls. Residual trauma-induced systemic inflammation and hepatocellular injury were not ameliorated by treatment with a polyclonal anti-HMGB1 antibody, even though HMGB1 levels were transiently elevated just 1 h after injury in both WT and C3H/HeJ mice. Collectively, these data demonstrate a critical role for a TLR4-HMGB1 pathway in the initiation of systemic inflammation and end-organ injury following isolated peripheral tissue injury.

Original languageEnglish
Pages (from-to)R1538-R1544
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number4
StatePublished - Oct 2007
Externally publishedYes


  • Damage-associated molecular pattern molecule
  • Danger signal
  • Femur fracture
  • Pattern recognition receptor
  • Tissue injury


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