Scavenger Receptor A Contributes To The Pathogenesis Of Fulminant Hepatitis Via Neutrophil Mediated Complement Activation

Fulminant hepatitis(FH)is a rare but acute disease characterized by rapid deterioration of hepatic functions,massive hepatocyte necrosis and hepatic encephalopathy.Despite the recent therapeutic advances,FH is still associated with significant mortality.Clinical evidences indicate that fibrin deposition and thrombosis within the microvasculature are now appreciated to play a pivotal role in the hepatocellular injury observed in human FH.Besides,accumulating evidence suggests that activation of immune cells and subsequent production of pro-inflammatory cytokines(i.e.TNF-?,IL-1?,IL-6,and IFN-?)play a critical role in the pathogenesis of FH.Therefore,exploring the immunological mechanisms of FH will provide ideas to develop more pervasive and efficient treatment of FH.Scavenger receptor A(SRA,also called CD204)is preferentially expressed on myeloid cells,such as macrophages and dendritic cells(DCs).Recently,Ozment et al reported that SRA presents on circulating and bone marrow neutrophils and was up-regulated in response to TLR2 stimulation.SRA acts as an innate pattern recognition receptor(PRR)capable of recognizing a broad spectrum of "self" and"non-self" ligands,thereby plays a significant role in host defense against foreign microbial infections and the maintenance of immune homeostasis.Importantly,emerging studies pointed out that SRA participated in the pathogenesis of multiple inflammatory diseases and its immunomodulatory function may be uncoupled from its endocytic/phagocytic activity.We found that SRA expression was highly up-regulated in FH patients infected with Hepatitis B Virus(HBV).However,its precise role in fulminant hepatitis(FH)has not been determined.Mouse hepatitis virus(MHV)is a positive strand RNA virus that causes a variety of diseases,including hepatitis,enteritis,and encephalitis in mice.Intraperitoneal infection of susceptible strains of mice(i.e.BALB/cJ and C57BL/6 mice)with hepatotropic MHV,such as MHV-3 and MHV-A59,results in sinusoidal thrombosis and hepatocellular necrosis,and thus,has served as a useful model for FH in humans.Compared with wild-type(WT)mice,SRA deficient mice were resistant to MHV-induced hepatitis,which was attributed to the suppressed inflammatory response and limited Fg12 expression.Treatment with C5aR antagonists(C5aRa)significantly reduced the liver damage and diminished the differences in inflammatory responses and liver injury between MHV-infected wild-type(WT)and SRA-/-mice,suggesting that SRA aggravates inflammation and liver damage via augmenting C5a production in the pathogenesis of FH.Interestingly,neutrophils were responsible for the difference in liver damage between MHV-A59 infected WT and SRA-/-mice.We further demonstrated that SRA efficiently enhanced TAK1 phosphorylation in neutrophils upon MHV-A59 stimulation,thereby promoting the activation of ERK pathway and subsequent NETosis formation and release of neutrophil elastase(NE);then,NE cleavaged C5 into C5a to exert proinflammatory effect.Sivelestat,a selective inhibitor of NE,abrogated the differences in production of C5a and hepatic injury between MHV-infected WT and SRA-/-mice.Moreover,we provided evidence that blockage of SRA attenuated the liver damage caused by MHV-A59 infection.Taken together,SRA enhanced the induction of NETosis of neutrophils upon MHV-A59 challenge,which promoted serum C5a generation in mice and subsequent acute liver damage.Furthermore,targeting SRA may be employed as a new immunotherapeutic strategy for FH.