FGL2/Fibroleukin mediates hepatic reperfusion injury by induction of sinusoidal endothelial cell and hepatocyte apoptosis in mice

Background & Aims: Sinusoidal endothelial cell (SEC) and hepatocyte death are early, TNF-alpha mediated events in ischemia and reperfusion of the liver (I/Rp). We previously reported that TNF-alpha induced liver injury is dependent on Fibrinogen like protein 2 (FGL2/Fibroleukin) and showed that FGL2 binding to its receptor, FccRIIB, results in lymphocyte apoptosis. In this study we examine whether I/Rp is induced by specific binding of FGL2 to Fc gamma RIIB expressed on SEC. Methods: Hepatic ischemia and reperfusion was induced in wild type (WT) mice and in mice with deletion or inhibition of FGL2 and FcRIIB. Liver injury was determined by AST release, necrosis and animal death. Apoptosis was evaluated with caspase 3 and TUNEL staining. Results: FGL2 deletion or inhibition resulted in decreased liver injury as determined by a marked reduction in both levels of AST and ALT and hepatocyte necrosis. Caspase 3 staining of SEC (12% vs. 75%) and hepatocytes (12% vs. 45%) as well as TUNEL staining of SEC (13% vs. 60%, p = 0.02) and hepatocytes (18% vs. 70%, p = 0.03), markers of apoptosis, were lower in Fgl2(-/-) compared to WT mice. In vitro incubation of SEC with FGL2 induced apoptosis of SEC from WT mice, but not Fc gamma RIIB-/- mice. Deletion of FccRIIB fully protected mice against SEC and hepatocyte death in vivo. Survival of mice deficient in either Fgl2(-/-)(80%) or Fc gamma RIIB-/- (100%) was markedly increased compared to WT mice (10%) which were subjected to 75 min of total hepatic ischemia (p = 0.001). Conclusions: FGL2 binding to the Fc gamma RIIB receptor expressed on SEC is a critical event in the initiation of the hepatic reperfusion injury cascade through induction of SEC and hepatocyte death. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.