Overproduction of Tenascin-C Driven by Lipid Accumulation in the Liver Aggravates Hepatic Ischemia/Reperfusion Injury in Steatotic Mice

The purpose of this study was to assess the significance of tenascin-C (Tnc) expression in steatotic liver ischemia/reperfusion injury (IRI). The critical shortage in donor organs has led to the use of steatotic livers in transplantation regardless of their elevated susceptibility to hepatic IRI. Tnc is an endogenous danger signal extracellular matrix molecule involved in various aspects of immunity and tissue injury. In the current study, mice were fed with a steatosis-inducing diet and developed approximately 50% hepatic steatosis, predominantly macrovesicular, before being subjected to hepatic IRI. We report here that lipid accumulation in hepatocytes inflated the production of Tnc in steatotic livers and in isolated hepatic stellate cells. Moreover, we show that the inability of Tnc–/– deficient steatotic mice to express Tnc significantly protected these mice from liver IRI. Compared with fatty controls, Tnc–/– steatotic mice showed significantly reduced serum transaminase levels and enhanced liver histological preservation at both 6 and 24 hours after hepatic IRI. The lack of Tnc expression resulted in impaired lymphocyte antigen 6 complex, locus (Ly6G) neutrophil and macrophage antigen-1 (Mac-1) leukocyte recruitment as well as in decreased expression of proinflammatory mediators (interleukin 1β, tumor necrosis factor α, and chemokine [C-X-C motif] ligand 2) after liver reperfusion. Myeloperoxidase (MPO) is the most abundant cytotoxic enzyme secreted by neutrophils and a key mediator of neutrophil-induced oxidative tissue injuries. Using an in vitro model of steatosis, we also show that Tnc markedly potentiated the effect of steatotic hepatocytes on neutrophil-derived MPO activity. In conclusion, our data support the view that inhibition of Tnc is a promising therapeutic approach to lessen inflammation in steatotic livers and to maximize their successful use in organ transplantation.