Abstract
Hepatocyte-specific HMGB1 deletion has been found to worsen the injury and inflammation in liver ischemia-reperfusion injury (IRI), highlighting a role for intracellular HMGB1 in cellular protection. Down-regulation of nuclear HMGB1 by small interfering RNA (siRNA) might not only decrease its injurious extracellular role by reducing its release but also serve to maintain its beneficial intracellular role, thus protecting against IRI. We established a non-lethal liver IRI model in mice via segmental hepatic warm ischemia for 1 h and reperfusion for 6 h. HMGB1-siRNA achieved a reduction of ~60–70% in the nuclear HMGB1 expression in the liver at 48 h post-treatment. Knockdown of nuclear HMGB1 expression dramatically reduced both the degree of nuclear-cytoplasmic translocation of HMGB1 during hepatic ischemia and of HMGB1 release after hepatic reperfusion, resulting in significant preservation of liver function and a marked reduction in pathological damage. Also, HMGB1-siRNA pretreatment markedly inhibited the increases in hepatic expression of TLR4, TLR2, RAGE, TNF-α, IL-1β, IL-6, MCP-1, iNOS, and COX-2 seen in control mice after hepatic reperfusion. We demonstrated for the first time that down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 release and protects against liver IRI, which is helpful for better understanding the role of HMGB1 in organ IRI.
Highlights
As an inevitable process that occurs during liver transplantation, ischemia-reperfusion injury (IRI) represents the main cause of graft dysfunction post-transplantation[1]
The silencing efficacy was evaluated by western blotting, real-time PCR, and immunohistochemical staining. Both western blotting and real-time PCR showed that the expression of High-mobility group box 1 (HMGB1) in the livers was significantly down-regulated after treatment with HMGB1siRNA (p < 0.01, vs. the normal untreated control group or scrambled Small interfering RNA (siRNA) group, Fig. 1A,B)
Extracellular HMGB1 has been recognized as a critical early mediator of injury and inflammation in organ IRI13,16,24
Summary
As an inevitable process that occurs during liver transplantation, ischemia-reperfusion injury (IRI) represents the main cause of graft dysfunction post-transplantation[1]. We have shown previously that carbon monoxide can protect against lethal renal IRI17 This remarkable protective effect is associated with significant prevention of nuclear-cytoplasmic translocation and release of HMGB1, indicating that a therapeutic tool capable of inhibiting its nuclear-cytoplasmic translocation and release from ischemic cells may have a potent and efficient protective effect on organ IRI. Hepatocyte-specific HMGB1 deletion worsens the injury and inflammation in liver I/R, resulting at least in part from increased DNA damage and nuclear instability, with a resulting increase in histone release[19]; the results of this study have suggested that HMGB1 might serve two very different roles after a sterile inflammatory insult, a beneficial intracellular role and an injurious extracellular role
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