Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells.
Endogenous ligands from damaged cells, so-called damage-associated molecular pattern molecules, can activate innate immunity via TLR4 signaling. Hepatic warm ischemia and reperfusion (I/R) injury and inflammation is largely TLR4 dependent. We produced TLR4 chimeric mice to assess whether the TLR4-dependent injury required TLR4 expression on liver parenchymal or nonparenchymal cells. Chimeric mice were produced by adoptive transfer of donor bone marrow cells into irradiated recipient animals using reciprocal combinations of TLR4 wild-type (WT; C3H/HeOuj) and TLR4 mutant (C3H/HeJ) mouse bone marrow. Wild-type chimeric mice bearing TLR4 mutant hemopoietic cells and TLR4 mutant mice transplanted with their own bone marrow-derived cells were protected from hepatic I/R and exhibited decreased JNK and NF-kappaB activation compared with WT chimeric mice transplanted with their own bone marrow. In contrast, TLR4 mutant mice transplanted with TLR4 WT bone marrow were not protected from liver I/R and demonstrated pronounced increases in JNK and NF-kappaB activation when compared with autochthonous transplanted mutant mice. In addition, depletion of phagocytes taking up gadolinium chloride failed to provide any additional protection to TLR4 mutant mice, but substantially reduced damage in WT mice after hepatic I/R. Together, these results demonstrate that TLR4 engagement on actively phagocytic nonparenchymal cells such as Kupffer cells is required for warm I/R-induced injury and inflammation in the liver.
Tsung
Allan
A
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Hoffman
Rosemary A
RA
Izuishi
Kunihiko
K
Critchlow
Nathan D
ND
Nakao
Atsunori
A
Chan
Meagan H
MH
Lotze
Michael T
MT
Geller
David A
DA
Billiar
Timothy R
TR
D000818:Animals; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000502:physiology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera
D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048670:MAP Kinase Kinase 4