Background/Aims: 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-κB 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. Conclusion: 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.
- Ischemia reperfusion injury
- Nuclear factor-kappaB (NF-κB)
- Phosphorylated c-Jun NH2-terminal kinase (CJUN)
- TLR4, knockout
- Tumor necrosis factor (TNF)-α