Ischemia and reperfusion liver injury is reduced in the absence of Toll-like receptor 4.
OBJECTIVE
Toll-like receptor 4 (TLR4) is expressed on hepatic non-parenchymal cells and hepatocytes. Hepatic signaling through TLR4 is critical in the pathogenesis of ischemia reperfusion injury (IRI) and leads to the release of cytokines. The role of bone marrow-derived TLR4 in the early reperfusion stage is unclear.


METHODS
We used wild type mice (WT), TLR4deficient (TLR4ko) mice and chimeras to dissociate between the role of TLR4 expression in the liver (TLR4ko/WT) and in the immuno-hematopoietic system (WT/TLR4ko) in mouse hepatic IR injury model. Mice were subjected to in vivo partial IRI (70% for 60 min).


RESULTS
Compared with WT IR livers, TLR4ko IRI mice (4 hours) showed a significant reduction in serum liver enzyme, hepatic TNF-α and interleukin-1β levels. Fewer apoptotic hepatocytes cells were identified by morphological criteria and immunohistochemistry for caspase-3. In TLR4ko mice, decreased hepatic CJUN and NF-ĸB expression during IRI was noted compared with WT mice. Chimeric mice having either TLR4 bone-marrow or non-bone marrow derived cells following IRI exhibited almost similar hepatic injury as WT mice in the immediate reperfusion stage.


CONCLUSIONS
Both TLR4 bone marrow-derived and non-bone marrow-derived cells are necessary in the initial process of hepatic injury. Activating TLR4-dependent signaling is required for IRI. The absence of the TLR4 gene plays a pivotal role in reducing hepatic IR injury.
Liver Disease Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. Ziv.Ben-Ari@sheba.health.gov.il
Ziv
Z
Ben-Ari
Oma
O
Avlas
Reut
R
Fallach
Hemda
H
Schmilovitz-Weiss
Yelena
Y
Chepurko
Orit
O
Pappo
Edith
E
Hochhauser
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000293:injuries* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3