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

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.

Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model

“…Recent studies have suggested that the initial damage to cells along with the activation of inflammatory signaling are involved the release of endogenous damage-associated molecular pattern (DAMP) signaling molecules from damaged/ischemic cells or IRI tissues. High mobility group box 1 (HMGB 1), a known DAMP molecule, can trigger cell-mediated inflammatory responses by enhancing the expression of TLR4 and increasing reactivity to it and other DAMP molecules 5 . HMGB1 was considered to be a novel key molecule during the IRI after KTx 6 .…”

Distinct contributions of CD4+T cell subsets in hepatic ischemia/reperfusion injury

“…Original magnification was ϫ50. other studies have demonstrated that dendritic cells are activated by Toll-like receptor-mediated pathway and increase their expression of MHC class II during hepatic I/R injury, leading to antigen-dependent activation of CD4 ϩ T cells (30,40). Moreover, blockade of TCR signaling with cyclosporine treatment is known to reduce hepatic I/R injury (24,35).…”

Ischemia–reperfusion and immediate T cell responses

“…Endothelial cells also express costimulatory molecules and can serve as APCs for T cell activation [86]. The important role of DCs in mediating immune responses in hepatic IRI was also reported in part by enhanced TLR4 reactivity [87]. TLRs are expressed abundantly on DCs and play a pivotal role in DC activation [68], which suggests a potential involvement of DC in the immune responses in IRI.…”