Search

Background and Aims: The outcomes of HBV infections are related to complex immune imbalances; however, the precise mechanisms by which HBV induces immune dysfunction are not well understood. Methods: HBV transgenic (HBs-Tg) mice were used to investigate intrahepatic NK cells in two distinct subsets: conventional NK (cNK) and liver-resident NK (LrNK) cells during a chronic HBV infection. Results: The cNK cells, but not the LrNK cells, were primarily responsible for the increase in the number of bulk NK cells in the livers of ageing HBs-Tg mice. The hepatic cNK cells showed a stronger ability to produce IL-10, coupled with a higher expression of CD69, TIGIT and PD-L1, and lower NKG2D expression in ageing HBs-Tg mice. A lower mitochondrial mass and membrane potential, and less polarized localization were observed in the hepatic cNK cells compared with the splenic cNK cells in the HBs-Tg mice. The enhanced galectin-3 (Gal-3) secreted from HBsAg+ hepatocytes accounted for the IL-10 production of hepatic cNK cells via ITGB1 signaling. For humans, LGALS3 and ITGB1 expression is positively correlated with IL-10 expression, and negatively correlated with the poor clinical progression of HCC. Conclusions: Gal-3-ITGB1 signaling shapes hepatic cNK cells but not LrNK cells during a chronic HBV infection, which may correlate with HCC progression. [ABSTRACT FROM AUTHOR]

Background & Aims: Non‐alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. The precise role of NK cells in the progression of NASH has yet to be elucidated. Methods: Using methionine‐ and choline‐deficient diets (MCD)‐induced NASH model, the role of NK cells was identified in WT mice compared with conventional NK cell–deficient Nfil3−/− mice. Results: After 8 weeks of MCD treatment, NASH was induced as shown by the significant macrovesicular steatosis, necro‐inflammation and fibrosis in the liver of WT B6 mice. In MCD‐treated WT B6 mice, the number of NK cells was markedly increased in the liver, but decreased in the spleen. Intrahepatic NK cells exhibited high levels of activation, as evidenced by the expression of CD107a and cytokine production of IFN‐γ, TGF‐β and IL‐10. Lower expression levels of Ki67 indicated a reduction in the proliferation of intrahepatic NK cells after MCD treatment. Increased expression of CXCL10 in the liver early after MCD treatment led to the increased recruitment of CXCR3+ NK cells into the liver. The MCD‐treated Nfil3−/− mice showed similar levels of TG and macrovesicular steatosis, thus more inflammatory infiltration and increased collagen deposition in the liver. Furthermore, the depletion of NK cells during MCD‐induced NASH caused a significant increase in the infiltration of monocyte‐derived macrophages (MoMFs) particularly Ly6Clo subsets towards M2. Conclusions: Intrahepatic NK cells, recruited through CXCL10‐CXCR3 interaction, play a protective role against the fibrosis progression in NASH, which provide us with a better understanding of the immunopathogenesis of NASH. [ABSTRACT FROM AUTHOR]

The appearance of donor-derived lymphocytes in liver transplant patients suggests that adult livers may contain cells capable of lymphopoiesis. However, only a few published studies have addressed the lymphopoietic capacity of adult liver cells, and its kinetics and features remain unclear. Herein, we investigated the lymphopoietic capacity of adult liver mononuclear cells (MNCs) and purified liver hematopoietic progenitor cells (HPCs) in vivo. Similar to bone-marrow transplantation (BMT), transplantation of liver MNCs alone was able to rescue survival of lethally irradiated mice. In terms of kinetics, liver MNC-derived myeloid lineage cells reconstituted more slowly than those from BMT. Liver MNC-derived lymphocyte lineage cells in the blood, spleen and BM also reconstituted more slowly than BMT, but lymphocytes in the liver recovered at a similar rate. Interestingly, liver MNCs predominantly gave rise to CD3+CD19− T cells in both irradiated WT and non-irradiated lymphocyte-deficient Rag-1−/−Il2rg−/− recipients. To define the lymphopoietic potential of various cell populations within liver MNCs, we transplanted purified lineage-negative (Lin−) liver HPCs into recipient mice. Unlike total liver MNCs, liver HPCs reconstituted T and B cells in similar frequencies to BMT. We further determined that the predominance of T cells observed after transplanting total liver MNCs likely originated from mature T cells, as purified donor liver T cells proliferated in the recipients and gave rise to CD8+ T cells. Thus, the capacity of donor adult liver cells to reconstitute lymphocytes in recipients derives from both HPCs and mature T cells contained in the liver MNC population. [ABSTRACT FROM AUTHOR]

Abstract: It is already clearly demonstrated that IFN-γ plays important roles in differentiation and maturation of T cells, B cells and macrophages; however, it is not clear whether NK cell development is regulated by IFN-γ. In our study by using IFN-γ-deficient mice (GKO), we observed that the percentage and number of NK1.1+CD3− cells were declined significantly in the liver, but not in the spleen, bone marrow and lymph node, of adult IFN-γ −/− mice. However, Lin−CD122+ NK progenitor cells developed normally both in liver and bone marrow in IFN-γ −/− mice. Moreover, more mature CD27−CD11b+ NK cells accumulated in the liver of IFN-γ −/− mice. Deficiency of IFN-γ resulted in the lower expression of CD69, GranzymeB and TRAIL by hepatic NK1.1+CD3− cells and the phenotypes of IFN-γ −/− hepatic NK1.1+CD3− cells were altered from WT hepatic NK cells. When stimulated with Poly (I:C) in vivo, attenuated accumulating in the liver and weaker expression of GranzymeB, TRAIL and FasL of NK1.1+CD3− cells were observed of IFN-γ −/− mice. Accordingly, these results demonstrate that IFN-γ plays important role in mounting liver environment for development of hepatic NK cells. [Copyright &y& Elsevier]

Abstract: Liver is the lymphoid organ with an overwhelming innate immune system, which functions as a filter organ at the first line between the digestive tract and the rest of the body, with receiving 80% of the blood supply through portal vein. TLRs are widely expressed on parenchymal and non-parenchymal cells in the liver, which play critical roles for the liver health. Recent studies indicate that TLR-medicated signals have been involved in almost all liver diseases such as acute and chronic hepatitis, liver fibrosis and cirrhosis, alcoholic and non-alcoholic liver disease, ischemia/reperfusion liver injury, liver regeneration and hepatocellular carcinoma. In this review, the expressions of TLRs in hepatic cell populations including hepatocytes, LSECs, Kupffer cells, lymphocytes, DCs, biliary epithelial cells and HSCs, and TLR ligands and signaling in the liver are summarized. Further, recent advances in the roles of TLRs in acute liver injury and regeneration as mediator and regulator, and their potential therapeutic targets are discussed. [Copyright &y& Elsevier]