Liver cancer is one of the most common malignancies,and various pathogenic factors can lead to its occurrence and development.Among all primary liver cancers,hepatocellular carcinoma(HCC)is the most common.With extens...Liver cancer is one of the most common malignancies,and various pathogenic factors can lead to its occurrence and development.Among all primary liver cancers,hepatocellular carcinoma(HCC)is the most common.With extensive studies,an increasing number of molecular mechanisms that promote HCC are being discovered.Surgical resection is still the most effective treatment for patients with early HCC.However,early detection and treatment are difficult for most HCC patients,and the postoperative recurrence rate is high,resulting in poor clinical prognosis of HCC.Although immunotherapy takes longer than conventional chemotherapy to produce therapeutic effects,it persists for longer.In recent years,the emergence of many new immunotherapies,such as immune checkpoint blockade and chimeric antigen receptor T cell therapies,has given new hope for the treatment of HCC.展开更多
Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit an...Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit and eliminate HBV,viral breakthrough may result due to non-adherence to treatment,the emergence of viral resistance,and a long treatment cycle.Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems.Therefore,understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control.This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.展开更多
BACKGROUND Fasudil,as a Ras homology family member A(RhoA)kinase inhibitor,is used to improve brain microcirculation and promote nerve regeneration clinically.Increasing evidence shows that Rho-kinase inhibition could...BACKGROUND Fasudil,as a Ras homology family member A(RhoA)kinase inhibitor,is used to improve brain microcirculation and promote nerve regeneration clinically.Increasing evidence shows that Rho-kinase inhibition could improve liver fibrosis.AIM To evaluate the anti-fibrotic effects of Fasudil in a mouse model of liver fibrosis induced by thioacetamide(TAA).METHODS C57BL/6 mice were administered TAA once every 3 d for 12 times.At 1 wk after induction with TAA,Fasudil was intraperitoneally injected once a day for 3 wk,followed by hematoxylin and eosin staining,sirius red staining,western blotting,and quantitative polymerase chain reaction(qPCR),and immune cell activation was assayed by fluorescence-activated cell sorting.Furthermore,the effects of Fasudil on hepatic stellate cells and natural killer(NK)cells were assayed in vitro.RESULTS First,we found that TAA-induced liver injury was protected,and the positive area of sirius red staining and type I collagen deposition were significantly decreased by Fasudil treatment.Furthermore,western blot and qPCR assays showed that the levels of alpha smooth muscle actin(α-SMA),matrix metalloproteinase 2(MMP-2),MMP-9,and transforming growth factor beta 1(TGF-β1)were inhibited by Fasudil.Moreover,flow cytometry analysis revealed that NK cells were activated by Fasudil treatment in vivo and in vitro.Furthermore,Fasudil directly promoted the apoptosis and inhibited the proliferation of hepatic stellate cells by decreasingα-SMA and TGF-β1.CONCLUSION Fasudil inhibits liver fibrosis by activating NK cells and blocking hepatic stellate cell activation,thereby providing a feasible solution for the clinical treatment of liver fibrosis.展开更多
γδ T cells are heterogeneous lymphocytes located in various tissues.However,a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associat...γδ T cells are heterogeneous lymphocytes located in various tissues.However,a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved.In this study,we performed single-cell RNA sequencing(scRNA-seq)to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples.We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors(pre-γδ T cells).The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments.The adoptive transfer of hematopoietic progenitor Lin^(-)Sca-1^(+)Mac-1^(+)(LSM)cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma^(+)(IFN-γ^(+))but not interleukin-17a^(+)(IL-17a^(+))γδ T cells in the liver.Importantly,thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner.These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells,which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.展开更多
Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus (HBV) infection remain unclear. Here, we report that exosomes present in the sera of chronic hep...Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus (HBV) infection remain unclear. Here, we report that exosomes present in the sera of chronic hepatitis B (CHB) patients contained both HBV nucleic acids and HBV proteins, and transferred HBV to hepatocytes in an active manner. Notably, HBV nucleic acids were detected in natural killer (NK) cells from both CHB patients and healthy donors after exposure to HBV-positive exosomes. Through real-time fluorescence microscopy and flow cytometry, 1, r-dioctadecyl-3,3,3',3',-tetramethylindodicarbocyanine, 4-chlorobenzenesulfnate salt (DiD)-Iabeled exosomes were observed to interact with NK cells and to be taken up by NK cells, which was enhanced by transforming growth factor-β treatment. Furthermore, HBV-positive exosomes impaired NK-cell functions, including interferon (IFN)-y production, cytolytic activity, NK-cell proliferation and survival, as well as the responsiveness of the cells to poly (I.C) stimulation. HBV infection suppressed the expression of pattern-recognition receptors, especially retinoic acid inducible gene I (RIG-I), on NK cells, resulting in the dampening of the nuclear factor KB (NF-KB) and p38 mitogen-activated protein kinase pathways. Our results highlight a previously unappreciated role of exosomes in HBV transmission and NK-cell dysfunction during CHB infection.展开更多
It is known that natural killer(NK)cell function is downregulated in chronic hepatitis B(CHB)-infected patients and in hepatic carcinoma(HCC)patients,but the mechanisms underlying this functional downregulation are la...It is known that natural killer(NK)cell function is downregulated in chronic hepatitis B(CHB)-infected patients and in hepatic carcinoma(HCC)patients,but the mechanisms underlying this functional downregulation are largely unclear.In this study,microRNA(miR)-146a expression increased in NK cells from CHB and HCC patients compared with NK cells from healthy donors,and miR-146a levels were negatively correlated to NK cell functions.Overexpression of miR-146a reduced NK cell-mediated cytotoxicity and the production of interferon(IFN)-γand tumor necrosis factor-α,which were reversed upon inhibition of miR-146a.In NK cells,miR-146a expression was induced by interleukin(IL)-10 and transforming growth factor-β,but reduced after treatment with interleukin-12,IFN-αand IFN-β.We further revealed that miR-146a regulated NK cell functions by targeting STAT1.Taken together,upregulated miR-146a expression,at least partially,attributes to NK cell dysfunction in CHB and HCC patients.Therefore,miR-146a may become a therapeutic target with great potential to ameliorate NK cell functions in liver disease.展开更多
Chronic hepatitis B(CHB)infection remains a serious public health problem worldwide;however,the relationship between cholesterol levels and CHB remains unclear.We isolated peripheral blood mononuclear cells from healt...Chronic hepatitis B(CHB)infection remains a serious public health problem worldwide;however,the relationship between cholesterol levels and CHB remains unclear.We isolated peripheral blood mononuclear cells from healthy blood donors and CHB patients to analyze free cholesterol levels,lipid raft formation,and cholesterol metabolism-related pathways.Hepatitis B virus(HBV)-carrier mice were generated and used to confirm changes in cholesterol metabolism and cell-surface lipid raft formation in dendritic cells(DCs)in the context of CHB.Additionally,HBV-carrier mice were immunized with a recombinant HBV vaccine(rHBVvac)combined with lipophilic statins and evaluated for vaccine efficacy against HBV.Serum samples were analyzed for HBsAg,anti-HBs,and alanine aminotransferase levels,and liver samples were evaluated for HBV DNA and RNA and HBcAg.CHB reduced free cholesterol levels and suppressed lipid raft formation on DCs in patients with CHB and HBV-carrier mice,whereas administration of lipophilic statins promoted free cholesterol accumulation and restored lipid rafts on DCs accompanied by an enhanced antigen-presentation ability in vitro and in vivo.Cholesterol accumulation on DCs improved the rHBVvac-mediated elimination of serum HBV DNA and intrahepatic HBV DNA,HBV RNA,and HBcAg and promoted the rHBVvac-mediated generation and polyfunctionality of HBV-specific CD11a^(hi) CD8α^(lo) cells,induction of the development of memory responses against HBV reinfection,and seroconversion from HBsAg to anti-HBs.The results demonstrated the important role of cholesterol levels in DC dysfunction during CHB,suggesting that strategies to increase cholesterol accumulation on DCs might enhance therapeutic vaccine efficacy against HBV and support development toward clinical CHB treatment.展开更多
Dear Editor,Growing evidence has indicated that heterologous COVID-19 vaccination could generate higher antibody(Ab)and cellmediated immune(CMI)responses than homologous vaccination regimen.1–3 However,fundamental un...Dear Editor,Growing evidence has indicated that heterologous COVID-19 vaccination could generate higher antibody(Ab)and cellmediated immune(CMI)responses than homologous vaccination regimen.1–3 However,fundamental understanding of immunological mechanisms dictating the enhanced vaccine immunity is still lacking.To gain mechanistic insights,we comprehensively profiled the immune responses generated by homologous or heterologous booster vaccination in mice(Fig.1a).展开更多
基金Supported by the Natural Science Foundation of China,No.81172789,30972692 and 81373222National Basic Research Program of China 973 Program,No.2013CB531503National Mega Project on Major Infectious Diseases Prevention and Treatment,No.2012ZX10002006
文摘Liver cancer is one of the most common malignancies,and various pathogenic factors can lead to its occurrence and development.Among all primary liver cancers,hepatocellular carcinoma(HCC)is the most common.With extensive studies,an increasing number of molecular mechanisms that promote HCC are being discovered.Surgical resection is still the most effective treatment for patients with early HCC.However,early detection and treatment are difficult for most HCC patients,and the postoperative recurrence rate is high,resulting in poor clinical prognosis of HCC.Although immunotherapy takes longer than conventional chemotherapy to produce therapeutic effects,it persists for longer.In recent years,the emergence of many new immunotherapies,such as immune checkpoint blockade and chimeric antigen receptor T cell therapies,has given new hope for the treatment of HCC.
基金Supported by National Science Foundation for Young Scientists of China, No.82001687National Major Science and Technology Project for Control and Prevention of Major Infectious Diseases, No.2018ZX10301401+2 种基金National Postdoctoral Program for Innovative Talents, No.BX20190192China Postdoctoral Science Foundation, No.2020M672064National Basic Research Program of China, No.2013CB531503
文摘Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit and eliminate HBV,viral breakthrough may result due to non-adherence to treatment,the emergence of viral resistance,and a long treatment cycle.Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems.Therefore,understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control.This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.
基金Supported by The National Natural Science Foundation of China,No.81972694 and No.81972686.
文摘BACKGROUND Fasudil,as a Ras homology family member A(RhoA)kinase inhibitor,is used to improve brain microcirculation and promote nerve regeneration clinically.Increasing evidence shows that Rho-kinase inhibition could improve liver fibrosis.AIM To evaluate the anti-fibrotic effects of Fasudil in a mouse model of liver fibrosis induced by thioacetamide(TAA).METHODS C57BL/6 mice were administered TAA once every 3 d for 12 times.At 1 wk after induction with TAA,Fasudil was intraperitoneally injected once a day for 3 wk,followed by hematoxylin and eosin staining,sirius red staining,western blotting,and quantitative polymerase chain reaction(qPCR),and immune cell activation was assayed by fluorescence-activated cell sorting.Furthermore,the effects of Fasudil on hepatic stellate cells and natural killer(NK)cells were assayed in vitro.RESULTS First,we found that TAA-induced liver injury was protected,and the positive area of sirius red staining and type I collagen deposition were significantly decreased by Fasudil treatment.Furthermore,western blot and qPCR assays showed that the levels of alpha smooth muscle actin(α-SMA),matrix metalloproteinase 2(MMP-2),MMP-9,and transforming growth factor beta 1(TGF-β1)were inhibited by Fasudil.Moreover,flow cytometry analysis revealed that NK cells were activated by Fasudil treatment in vivo and in vitro.Furthermore,Fasudil directly promoted the apoptosis and inhibited the proliferation of hepatic stellate cells by decreasingα-SMA and TGF-β1.CONCLUSION Fasudil inhibits liver fibrosis by activating NK cells and blocking hepatic stellate cell activation,thereby providing a feasible solution for the clinical treatment of liver fibrosis.
基金supported by grants from the National Natural Science Foundation of China(91842305,81771686)the National Key R&D Program of China(2019YFA0508503)+1 种基金the National Major Science&Technology Project for Control and Prevention of Major Infectious Diseases in China(2018ZX10301401)the Shandong Provincial Key Research and Development Program(Major Scientific and Technological Innovation Project)(2019JZZY021013).
文摘γδ T cells are heterogeneous lymphocytes located in various tissues.However,a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved.In this study,we performed single-cell RNA sequencing(scRNA-seq)to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples.We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors(pre-γδ T cells).The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments.The adoptive transfer of hematopoietic progenitor Lin^(-)Sca-1^(+)Mac-1^(+)(LSM)cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma^(+)(IFN-γ^(+))but not interleukin-17a^(+)(IL-17a^(+))γδ T cells in the liver.Importantly,thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner.These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells,which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.
基金This work was supported by grants from the National Basic Research Program of China (No. 2013CB531503), the Natural Science Foundation of China (Nos. 81172789 and 30972692).
文摘Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus (HBV) infection remain unclear. Here, we report that exosomes present in the sera of chronic hepatitis B (CHB) patients contained both HBV nucleic acids and HBV proteins, and transferred HBV to hepatocytes in an active manner. Notably, HBV nucleic acids were detected in natural killer (NK) cells from both CHB patients and healthy donors after exposure to HBV-positive exosomes. Through real-time fluorescence microscopy and flow cytometry, 1, r-dioctadecyl-3,3,3',3',-tetramethylindodicarbocyanine, 4-chlorobenzenesulfnate salt (DiD)-Iabeled exosomes were observed to interact with NK cells and to be taken up by NK cells, which was enhanced by transforming growth factor-β treatment. Furthermore, HBV-positive exosomes impaired NK-cell functions, including interferon (IFN)-y production, cytolytic activity, NK-cell proliferation and survival, as well as the responsiveness of the cells to poly (I.C) stimulation. HBV infection suppressed the expression of pattern-recognition receptors, especially retinoic acid inducible gene I (RIG-I), on NK cells, resulting in the dampening of the nuclear factor KB (NF-KB) and p38 mitogen-activated protein kinase pathways. Our results highlight a previously unappreciated role of exosomes in HBV transmission and NK-cell dysfunction during CHB infection.
基金supported by grants from National Natural Science Foundation of China(No.81172789,81373222 and 31200651)National Mega Project on Major Infectious Diseases Prevention and Treatment(No.2012ZX10002006).
文摘It is known that natural killer(NK)cell function is downregulated in chronic hepatitis B(CHB)-infected patients and in hepatic carcinoma(HCC)patients,but the mechanisms underlying this functional downregulation are largely unclear.In this study,microRNA(miR)-146a expression increased in NK cells from CHB and HCC patients compared with NK cells from healthy donors,and miR-146a levels were negatively correlated to NK cell functions.Overexpression of miR-146a reduced NK cell-mediated cytotoxicity and the production of interferon(IFN)-γand tumor necrosis factor-α,which were reversed upon inhibition of miR-146a.In NK cells,miR-146a expression was induced by interleukin(IL)-10 and transforming growth factor-β,but reduced after treatment with interleukin-12,IFN-αand IFN-β.We further revealed that miR-146a regulated NK cell functions by targeting STAT1.Taken together,upregulated miR-146a expression,at least partially,attributes to NK cell dysfunction in CHB and HCC patients.Therefore,miR-146a may become a therapeutic target with great potential to ameliorate NK cell functions in liver disease.
基金supported by the National Key Research and Development Programme (2021YFC2300603)the National Postdoctoral Programme for Innovative Talents (No.BX20190192)+1 种基金the China Postdoctoral Science Foundation (No.2020M672064)the National Science Foundation for Young Scientists of China (No.82001687).
文摘Chronic hepatitis B(CHB)infection remains a serious public health problem worldwide;however,the relationship between cholesterol levels and CHB remains unclear.We isolated peripheral blood mononuclear cells from healthy blood donors and CHB patients to analyze free cholesterol levels,lipid raft formation,and cholesterol metabolism-related pathways.Hepatitis B virus(HBV)-carrier mice were generated and used to confirm changes in cholesterol metabolism and cell-surface lipid raft formation in dendritic cells(DCs)in the context of CHB.Additionally,HBV-carrier mice were immunized with a recombinant HBV vaccine(rHBVvac)combined with lipophilic statins and evaluated for vaccine efficacy against HBV.Serum samples were analyzed for HBsAg,anti-HBs,and alanine aminotransferase levels,and liver samples were evaluated for HBV DNA and RNA and HBcAg.CHB reduced free cholesterol levels and suppressed lipid raft formation on DCs in patients with CHB and HBV-carrier mice,whereas administration of lipophilic statins promoted free cholesterol accumulation and restored lipid rafts on DCs accompanied by an enhanced antigen-presentation ability in vitro and in vivo.Cholesterol accumulation on DCs improved the rHBVvac-mediated elimination of serum HBV DNA and intrahepatic HBV DNA,HBV RNA,and HBcAg and promoted the rHBVvac-mediated generation and polyfunctionality of HBV-specific CD11a^(hi) CD8α^(lo) cells,induction of the development of memory responses against HBV reinfection,and seroconversion from HBsAg to anti-HBs.The results demonstrated the important role of cholesterol levels in DC dysfunction during CHB,suggesting that strategies to increase cholesterol accumulation on DCs might enhance therapeutic vaccine efficacy against HBV and support development toward clinical CHB treatment.
基金supported by the Fundamental Research Funds for the Central Universities(2632022YC01,to A.L.)Research Start-up Funds from China Pharmaceutical University(3150120048,to A.L)+2 种基金Shanghai Pujiang Talent Program(2020PJD068,to A.L)the National Natural Science Foundation of China(82061138008,to W.T.)Beijing Municipal Science and Technology Project(Z211100002521017).
文摘Dear Editor,Growing evidence has indicated that heterologous COVID-19 vaccination could generate higher antibody(Ab)and cellmediated immune(CMI)responses than homologous vaccination regimen.1–3 However,fundamental understanding of immunological mechanisms dictating the enhanced vaccine immunity is still lacking.To gain mechanistic insights,we comprehensively profiled the immune responses generated by homologous or heterologous booster vaccination in mice(Fig.1a).