Role And Regulatory Mechanism Of Macrophages In Liver Injury

Liver has a large innate immune system,innate immune cells are activated when liver is infected.They clean up pathogens and are also involved in liver injury.These activated immune cells are also regulated by regulatory cells,preventing excessive liver injury.Our group mainly study phenotype and function of CD205⁺macrophages in hepatitis B virus（HBV）infected liver and regulation of B1 cells on pro-inflammatory Ly6C^hi macrophages in Schistosoma japonicum infected liver.Our previous study found that HBs-Tg hepatic CD205⁺macrophages increased significantly compared with those in B6 mice,and these increased CD205⁺macrophages resulted in HBs-Tg mice to produce a large number of inflammatory cytokines（IL-12,TNF-α）after CpG stimulation and severe liver injury,indicating that CD205⁺macrophages are involved in HBV infected liver inflammation.Further identification of CD205⁺macrophages in this study,we found that HBs-Tg mice hepatic CD205⁺macrophages were activated and expressed high levels of costimulatory molecules（CD40,CD80,CD86）.Furthermore,hepatic CD205⁺macrophages from HBs-Tg mice expressed higher levels of inflammatory cytokine genes（Tnfα,Il6,Il10,Il12）,chemokine genes（Cxcl2,Ccl2,Ccl3,Ccl4,Ccl24）,and phagocytosis-related genes（Cd5l,Macro,Gpnmb,Trem2,Axl）than hepatic CD205^-macrophages.Moreover,we confirmed our results in the liver of patients with chronic hepatitis B（CHB）.Compared with healthy controls,hepatic CD205⁺macrophages in patients with CHB increased significantly.Expression levels of activation markers（CD14,CD16,HLA-DR）and inflammatory cytokines（IL-12,TNF-α）were also significantly increased in CHB patients hepatic CD205⁺macrophages.Our data suggest that increased hepatic CD205⁺macrophages are activated observed during HBV infection.They are more sensitive to stimulation of bacterial DNA,and secrete a large number of inflammatory cytokines,thereby mediating liver injury.In Schistosoma japonicum infected murine model,we found that B cell-deficient（μMT）mice showed showed aggravated liver pathology than wild-type（WT）mice.In addition,μMT mice hepatic pro-inflammatory Ly6C^hi macrophages increased significantly and expressed higher levels of Ccl1,Ccl2,Ccl3,Ccl4 and Ccl5 which can recruit Ly6C^hi monocytes than those in WT mice.Further flow cytometric analysis showed that hepatic B1 cells increased and peritoneal cavity（PC）B1 cells decreased in infected WT mice.Transferring WT mice-derived PC B cells(not Il10^-/-mice-derived PC B cells)toμMT mice could significantly reduce liver pathology and inhibit expression of chemokines and inflammatory cytokines and infiltration of Ly6C^hii macrophages in the liver.We also found that secretion of IL-10 from hepatic B cells increased significantly and IL-10 mainly derived from B1 cells in infected WT mice.Taken together,our data conclude that PC B1 cells can migtrate into the liver and secreting IL-10 when liver is damaged,on the one hand,inhibiting expression of CCL2,CCL3 and then inhibiting excessive infiltration of Ly6C^hi macrophages into the liver;on the other hand,restricting expression of IL-6 and TNF-α,thereby alleviating liver early inflammation and later fibrosis.Taken together,our research elaborates the role and regulatory mechanism of macrophages in liver injury,providing a theoretical evidence for future immunotherapy of liver diseases with targeting macrophages.