Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury

Allan Tsung, Ning Zheng, Geetha Jeyabalan, Kunihiko Izuishi, John R. Klune, David A. Geller, Michael T. Lotze, Lina Lu, Timothy R. Billiar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


Endogenous ligands released from damaged cells, so-called damage-associated molecular pattern molecules (DAMPs), activate innate signaling pathways including the TLRs. We have shown that hepatic, warm ischemia and reperfusion (I/R) injury, generating local, noninfectious DAMPs, promotes inflammation, which is largely TLR4-dependent. Here, we demonstrate that increasing dendritic cell (DC) numbers enhance inflammation and organ injury after hepatic I/R. High-mobility group box 1 (HMGB1), a NF released by necrotic cells or secreted by stimulated cells, is one of a number of ligands promoting TLR4 reactivity. Augmentation of DC numbers in the liver with GM-CSF hydrodynamic transfection significantly increased liver damage after I/R when compared with controls. TLR4 engagement on hepatic DC was required for the I/R-induced injury, as augmentation of DC numbers in TLR4 mutant (C3H/HeJ) mice did not worsen hepatic damage. It is interesting that TLR4 expression was increased in hepatic DC following HMGB1 stimulation in vitro, suggesting a mechanism for the increased liver injury following I/R. It thus appears that functional TLR4 on DC is required for I/R-induced injury. Furthermore, HMGB1 may direct the inflammatory responses mediated by DC, at least in part, by enhancing TLR4 expression and reactivity to it and other DAMPs.

Original languageEnglish
Pages (from-to)119-128
Number of pages10
JournalJournal of Leukocyte Biology
Issue number1
StatePublished - Jan 2007
Externally publishedYes


  • Inflammation
  • Liver
  • Toll-like receptor 4


Dive into the research topics of 'Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury'. Together they form a unique fingerprint.

Cite this