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

• Published in: Journal of leukocyte biology Vol. 81; no. 1; pp. 119 - 128
• Main Authors: Tsung, Allan, Zheng, Ning, Jeyabalan, Geetha, Izuishi, Kunihiko, Klune, John R., Geller, David A., Lotze, Michael T., Lu, Lina, Billiar, Timothy R.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.01.2007
• Subjects: Animals; Dendritic Cells - physiology; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Hepatocytes - physiology; HMGB1 Protein - pharmacology; inflammation; liver; Liver - cytology; Liver - metabolism; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Signal Transduction; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-Like Receptor 4 - physiology; Toll‐like receptor 4; Transfection
• DOI: 10.1189/jlb.0706468
• ISSN: 0741-5400

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.