Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury
Open Access
- 24 October 2006
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 81 (1), 119-128
- https://doi.org/10.1189/jlb.0706468
Abstract
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.Keywords
Funding Information
- American College of Surgeons Resident Scholarship
- NIH (R01-GM37631)
- 1 PO1 CA (101944-01)
- M. T. L. (R01-GM52021)
- D. A. G. (R01-GM50441, P50-GM53789)
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