Hepatitis B Virus Infection and Immunopathogenesis in a Humanized Mouse Model: Induction of Human-Specific Liver Fibrosis and M2-Like Macrophages

English version České info

Over 350 million people worldwide are chronically infected with the hepatitis B virus (HBV), which leads to severe liver diseases including fibrosis and cancer. The mechanisms of chronic HBV infection and disease are poorly understood due to a lack of a robust small animal model. Here we report a novel animal model that can be efficiently repopulated with both human immune and liver cells. The A2/NSG-hu HSC/Hep humanized mouse model supported persistent HBV infection, human immune responses, albeit impaired in the liver, chronic liver inflammation and liver fibrosis. In addition, we found that the HBV mediated liver immune impairment and liver disease was associated with high level of infiltrated human immuno-suppressive/pro-fibrogenic macrophages; this result was confirmed in chronic HBV-induced liver disease patients and acute HBV – induced liver failure patients. Importantly, we demonstrate that HBV promotes immuno-suppressive/pro-fibrogenic macrophage polarization in human macrophages using cell culture models. The humanized mouse model is a valuable platform in studying HBV infection, human immune response and liver diseases. Furthermore, results from this study suggest a critical role for macrophage activation in hepatitis B induced liver diseases, thus providing a novel therapeutic target.

Vyšlo v časopise: Hepatitis B Virus Infection and Immunopathogenesis in a Humanized Mouse Model: Induction of Human-Specific Liver Fibrosis and M2-Like Macrophages. PLoS Pathog 10(3): e32767. doi:10.1371/journal.ppat.1004032
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004032

Souhrn

Zdroje

1. ZhangZ, ZhangF, AnP, GuoX, ShenY, et al. (2011) Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118: 1912–1922.

2. ChoiJG, ChungYH, KimJA, JinYJ, ParkWH, et al. (2012) High HBV-DNA titer in surrounding liver rather than in hepatocellular carcinoma tissue predisposes to recurrence after curative surgical resection. J Clin Gastroenterol 46: 413–419.

3. HeathcoteEJ (2008) Demography and presentation of chronic hepatitis B virus infection. Am J Med 121: S3–11.

4. YeungLT, RobertsEA (2010) Current issues in the management of paediatric viral hepatitis. Liver Int 30: 5–18.

5. RehermannB (2007) Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses. Semin Liver Dis 27: 152–160.

6. TanYJ (2011) Hepatitis B virus infection and the risk of hepatocellular carcinoma. World J Gastroenterol 17: 4853–4857.

7. FuJ, XuD, LiuZ, ShiM, ZhaoP, et al. (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132: 2328–2339.

8. NissimO, MelisM, DiazG, KleinerDE, TiceA, et al. (2012) Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling. PLoS One 7: e49611.

9. FarciP, DiazG, ChenZ, GovindarajanS, TiceA, et al. (2010) B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus-associated acute liver failure. Proc Natl Acad Sci U S A 107: 8766–8771.

10. DandriM, LutgehetmannM, PetersenJ (2013) Experimental models and therapeutic approaches for HBV. Semin Immunopathol 35: 7–21.

11. GilgenkrantzH (2011) [Humanized mice for the study of hepatitis C]. Med Sci (Paris) 27: 587–589.

12. de JongYP, RiceCM, PlossA (2010) New horizons for studying human hepatotropic infections. J Clin Invest 120: 650–653.

13. BrezillonN, BrunelleMN, MassinetH, GiangE, LamantC, et al. (2011) Antiviral Activity of Bay 41-4109 on Hepatitis B Virus in Humanized Alb-uPA/SCID Mice. PLoS One 6: e25096.

14. MercerDF, SchillerDE, ElliottJF, DouglasDN, HaoC, et al. (2001) Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7: 927–933.

15. AzumaH, PaulkN, RanadeA, DorrellC, Al-DhalimyM, et al. (2007) Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 25: 903–910.

16. BissigKD, LeTT, WoodsNB, VermaIM (2007) Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci U S A 104: 20507–20511.

17. BissigKD, WielandSF, TranP, IsogawaM, LeTT, et al. (2010) Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest 120: 924–930.

18. WashburnML, BilityMT, ZhangL, KovalevGI, BuntzmanA, et al. (2011) A Humanized Mouse Model to Study Hepatitis C Virus Infection, Immune Response, and Liver Disease. Gastroenterology 140: 1334–1344.

19. RobinetE, BaumertTF (2011) A first step towards a mouse model for hepatitis C virus infection containing a human immune system. J Hepatol 55: 718–720.

20. WangS, ChenZ, HuC, QianF, ChengY, et al. (2013) Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 production in monocytes/macrophages by interfering with JNK activation. J Immunol 190: 5142–5151.

21. ShiB, RenG, HuY, WangS, ZhangZ, et al. (2012) HBsAg inhibits IFN-alpha production in plasmacytoid dendritic cells through TNF-alpha and IL-10 induction in monocytes. PLoS One 7: e44900.

22. OquendoJ, DubanchetS, CapelF, MabitH, PetitMA (1996) Suppressive effect of hepatitis B virus on the induction of interleukin-1 beta and interleukin-6 gene expression in the THP-1 human monocytic cell line. Eur Cytokine Netw 7: 793–800.

23. BragaTT, Correa-CostaM, GuiseYF, CastoldiA, De OliveiraCD, et al. (2012) MyD88 Signaling Pathway Is Involved in Renal Fibrosis by Favoring a T(H)2 Immune Response and Activating Alternative M2 Macrophages. Mol Med 18: 1231–1239.

24. GlimJE, NiessenFB, EvertsV, van EgmondM, BeelenRH (2012) Platelet derived growth factor-CC secreted by M2 macrophages induces alpha-smooth muscle actin expression by dermal and gingival fibroblasts. Immunobiology 218(6): 924–9.

25. PereiraTA, XieG, ChoiSS, SynWK, VoietaI, et al. (2013) Macrophage-derived hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int 33: 149–161.

26. KuraharaH, TakaoS, MaemuraK, MatakiY, KuwahataT, et al. (2013) M2-Polarized Tumor-Associated Macrophage Infiltration of Regional Lymph Nodes Is Associated With Nodal Lymphangiogenesis and Occult Nodal Involvement in pN0 Pancreatic Cancer. Pancreas 42: 155–159.

27. ShirabeK, ManoY, MutoJ, MatonoR, MotomuraT, et al. (2012) Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg Today 42: 1–7.

28. ChoiB, ChunE, KimM, KimSY, KimST, et al. (2011) Human T cell development in the liver of humanized NOD/SCID/IL-2Rgamma(null)(NSG) mice generated by intrahepatic injection of CD34(+) human (h) cord blood (CB) cells. Clin Immunol 139: 321–335.

29. AndreMC, ErbacherA, GilleC, SchmaukeV, GoeckeB, et al. (2010) Long-term human CD34+ stem cell-engrafted nonobese diabetic/SCID/IL-2R gamma(null) mice show impaired CD8+ T cell maintenance and a functional arrest of immature NK cells. J Immunol 185: 2710–2720.

30. ShultzLD, SaitoY, NajimaY, TanakaS, OchiT, et al. (2010) Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci U S A 107: 13022–13027.

31. TraggiaiE, ChichaL, MazzucchelliL, BronzL, PiffarettiJC, et al. (2004) Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304: 104–107.

32. WilsonJH, PaturzoFX, JohnsonLK, CarreiroMP, HixsonDC, et al. (2006) Rat hepatocyte engraftment in severe combined immunodeficient×beige mice using mouse-specific anti-fas antibody. Xenotransplantation 13: 53–62.

33. VidalI, BlanchardN, AlexandreE, GandilletA, Chenard-NeuMP, et al. (2008) Improved xenogenic hepatocyte implantation into nude mouse liver parenchyma with acute liver failure when followed by repeated anti-Fas antibody (Jo2) treatment. Cell Transplant 17: 507–524.

34. GuidottiJE, MalletVO, ParlierD, MitchellC, FabreM, et al. (2001) Fas/CD95 pathway induces mouse liver regeneration and allows for highly efficient retrovirus-mediated gene transfer. Hepatology 33: 10–15.

35. NishimuraY, HirabayashiY, MatsuzakiY, MusetteP, IshiiA, et al. (1997) In vivo analysis of Fas antigen-mediated apoptosis: effects of agonistic anti-mouse Fas mAb on thymus, spleen and liver. Int Immunol 9: 307–316.

36. MignonA, GuidottiJE, MitchellC, FabreM, WernetA, et al. (1998) Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes. Nat Med 4: 1185–1188.

37. ChenQ, HeF, KwangJ, ChanJK, ChenJ (2012) GM-CSF and IL-4 stimulate antibody responses in humanized mice by promoting T, B, and dendritic cell maturation. J Immunol 189: 5223–5229.

38. ArzumanyanA, ReisHM, FeitelsonMA (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 13: 123–135.

39. QuattroniP (2011) Liver: Usefulness of noninvasive biomarkers of fibrosis in chronic liver disease. Nat Rev Gastroenterol Hepatol 8: 659.

40. MurrayPJ, WynnTA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11: 723–737.

41. SicaA, MantovaniA (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122: 787–795.

42. KawabataH, SetoguchiT, YoneK, SoudaM, YoshidaH, et al. (2010) High mobility group box 1 is upregulated after spinal cord injury and is associated with neuronal cell apoptosis. Spine (Phila Pa 1976) 35: 1109–1115.

43. FengY, YangQ, XuJ, QianG, LiuY (2008) Effects of HMGB1 on PMN apoptosis during LPS-induced acute lung injury. Exp Mol Pathol 85: 214–222.

44. WuH, ChenG, WyburnKR, YinJ, BertolinoP, et al. (2007) TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest 117: 2847–2859.

45. ReinhardL, RuppC, RiedelHD, RuppertT, GieseT, et al. (2012) S100A9 is a biliary protein marker of disease activity in primary sclerosing cholangitis. PLoS One 7: e29821.

46. SimardJC, CesaroA, Chapeton-MontesJ, TardifM, AntoineF, et al. (2013) S100A8 and S100A9 induce cytokine expression and regulate the NLRP3 inflammasome via ROS-dependent activation of NF-kappaB(1.). PLoS One 8: e72138.

47. VanlandschootP, RoobrouckA, Van HoutteF, Leroux-RoelsG (2002) Recombinant HBsAg, an apoptotic-like lipoprotein, interferes with the LPS-induced activation of ERK-1/2 and JNK-1/2 in monocytes. Biochem Biophys Res Commun 297: 486–491.

48. ChengJ, ImanishiH, MorisakiH, LiuW, NakamuraH, et al. (2005) Recombinant HBsAg inhibits LPS-induced COX-2 expression and IL-18 production by interfering with the NFkappaB pathway in a human monocytic cell line, THP-1. J Hepatol 43: 465–471.

49. VanlandschootP, Van HoutteF, RoobrouckA, FarhoudiA, Leroux-RoelsG (2002) Hepatitis B virus surface antigen suppresses the activation of monocytes through interaction with a serum protein and a monocyte-specific receptor. J Gen Virol 83: 1281–1289.

50. MeulemanP, Leroux-RoelsG (2008) The human liver-uPA-SCID mouse: a model for the evaluation of antiviral compounds against HBV and HCV. Antiviral Res 80: 231–238.

51. ZenderL, HutkerS, LiedtkeC, TillmannHL, ZenderS, et al. (2003) Caspase 8 small interfering RNA prevents acute liver failure in mice. Proc Natl Acad Sci U S A 100: 7797–7802.

52. ShultzLD, IshikawaF, GreinerDL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7: 118–130.

53. HaridassD, YuanQ, BeckerPD, CantzT, IkenM, et al. (2009) Repopulation efficiencies of adult hepatocytes, fetal liver progenitor cells, and embryonic stem cell-derived hepatic cells in albumin-promoter-enhancer urokinase-type plasminogen activator mice. Am J Pathol 175: 1483–1492.

54. MitchellT, ArmstrongGL, HuDJ, WasleyA, PainterJA (2011) The increasing burden of imported chronic hepatitis B - United States, 1974–2008. PLoS One 6: e27717.

55. KimBK, RevillPA, AhnSH (2011) HBV genotypes: relevance to natural history, pathogenesis and treatment of chronic hepatitis B. Antivir Ther 16: 1169–1186.

56. JiangQ, ZhangL, WangR, JeffreyJ, WashburnML, et al. (2008) FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2−/−gammaC−/− mice in vivo. Blood 112: 2858–2868.

57. SchmelzerE, WauthierE, ReidLM (2006) The phenotypes of pluripotent human hepatic progenitors. Stem Cells 24: 1852–1858.

58. ZhangL, KovalevGI, SuL (2007) HIV-1 infection and pathogenesis in a novel humanized mouse model. Blood 109: 2978–2981.

59. PajvaniUB, TrujilloME, CombsTP, IyengarP, JelicksL, et al. (2005) Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 11: 797–803.

60. LinM, ChenQ, YangLY, LiWY, CaoXB, et al. (2007) Hepatitis B virus infection and replication in primarily cultured human fetal hepatocytes. World J Gastroenterol 13: 1027–1031.

61. SugiyamaM, TanakaY, KurbanovF, MaruyamaI, ShimadaT, et al. (2009) Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mouse with human hepatocytes. Gastroenterology 136: 652–e653, 652-662, e653.

62. KnodellRG, IshakKG, BlackWC, ChenTS, CraigR, et al. (1981) Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1: 431–435.

63. LindhG, WeilandO, GlaumannH (1988) The application of a numerical scoring system for evaluating the histological outcome in patients with chronic hepatitis B followed in long-term. Hepatology 8: 98–103.

64. ZouZ, XuD, LiB, XinS, ZhangZ, et al. (2009) Compartmentalization and its implication for peripheral immunologically-competent cells to the liver in patients with HBV-related acute-on-chronic liver failure. Hepatol Res 39: 1198–1207.

65. ZhangZ, ChenD, YaoJ, ZhangH, JinL, et al. (2007) Increased infiltration of intrahepatic DC subsets closely correlate with viral control and liver injury in immune active pediatric patients with chronic hepatitis B. Clin Immunol 122: 173–180.