Toll‐Like Receptor and Heme Oxygenase‐1 Signaling in Hepatic Ischemia/Reperfusion Injury

Abstract

Ischemia/reperfusion injury (IRI) represents the major problem in clinical liver transplantation. We have shown that toll‐like receptor 4 (TLR4) signaling is specifically required in initiating antigen‐independent IRI leading to liver inflammation, whereas local induction of anti‐oxidant heme oxygenase‐1 (HO‐1) is cytoprotective. This study analyzes in vivo interactions between HO‐1 and sentinel TLR system in the pathophysiology of liver IRI. Using a 90‐min lobar warm ischemia model, wild type (WT), TLR4 KO/mutant and TLR2 KO mice were first assessed for the severity of hepatocellular damage at 6 h postreperfusion. Unlike in WT or TLR2‐deficient mice, disruption/absence of TLR4 pathway reduced IRI, as manifested by liver function (serum alanine aminotransferase levels), histology (Suzuki's scores), neutrophil infiltration (myeloperoxidase activity) and local/systemic TNF‐α production (mRNA/protein levels). Moreover, defective TLR4 but not TLR2 signaling increased mRNA/protein HO‐1 expression. In contrast, tin protoporphyrin‐mediated HO‐1 inhibition restored hepatic damage in otherwise IRI‐resistant TLR4 mutant/KO mice. CoPP‐induced HO‐1 overexpression ameliorated hepatic damage in IRI‐susceptible TLR2 KO mice, comparable with WT controls, and concomitantly diminished TLR4 levels. In conclusion, this study highlights the importance of cross talk between HO‐1 and TLR system in the mechanism of hepatic IRI. Hepatic IRI represents a case for innate immunity in which HO‐1 modulates proinflammatory responses that are triggered via TLR4 signaling, a putative HO‐1 repressor. Ischemia/reperfusion injury (IRI) represents the major problem in clinical liver transplantation. We have shown that toll‐like receptor 4 (TLR4) signaling is specifically required in initiating antigen‐independent IRI leading to liver inflammation, whereas local induction of anti‐oxidant heme oxygenase‐1 (HO‐1) is cytoprotective. This study analyzes in vivo interactions between HO‐1 and sentinel TLR system in the pathophysiology of liver IRI. Using a 90‐min lobar warm ischemia model, wild type (WT), TLR4 KO/mutant and TLR2 KO mice were first assessed for the severity of hepatocellular damage at 6 h postreperfusion. Unlike in WT or TLR2‐deficient mice, disruption/absence of TLR4 pathway reduced IRI, as manifested by liver function (serum alanine aminotransferase levels), histology (Suzuki's scores), neutrophil infiltration (myeloperoxidase activity) and local/systemic TNF‐α production (mRNA/protein levels). Moreover, defective TLR4 but not TLR2 signaling increased mRNA/protein HO‐1 expression. In contrast, tin protoporphyrin‐mediated HO‐1 inhibition restored hepatic damage in otherwise IRI‐resistant TLR4 mutant/KO mice. CoPP‐induced HO‐1 overexpression ameliorated hepatic damage in IRI‐susceptible TLR2 KO mice, comparable with WT controls, and concomitantly diminished TLR4 levels. In conclusion, this study highlights the importance of cross talk between HO‐1 and TLR system in the mechanism of hepatic IRI. Hepatic IRI represents a case for innate immunity in which HO‐1 modulates proinflammatory responses that are triggered via TLR4 signaling, a putative HO‐1 repressor.