title: Feedback regulation of IFN-α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity.
abstract: Hepatitis B virus (HBV) is known to cause age-dependent infection outcomes wherein most infections during young age result in chronicity. The mechanism underlying the differential outcome remains elusive. By using hydrodynamic injection of the replication-competent pAAV-HBV, we established a mouse model in which HBV persistence was generated in 4-5 w/o C57BL/6 young mice, but not in adult mice over 10 w/o. HBV-tolerant young mice expressed higher interferon (IFN)-α/β levels in hepatocytes and intrahepatic plasmacytoid DCs (pDCs) than adult mice after pAAV-HBV injection. Excessive IFN-α/β expression in young mice was associated with induction of the Axl regulatory pathway and expansion of intrahepatic Treg cells. In line with these findings, augmented IFN-β expression increased Axl expression in the liver and HBV persistence in adult mice, whereas IFN-α/β signaling blockage decreased Axl expression and HBV persistence in young mice. Accordingly, Axl overexpression decreased HBV clearance of adult mice whereas Axl silencing enhanced HBV clearance of young mice. In vitro, IFN-β priming of pDCs and Axl-overexpressing macrophages enhanced Treg-cell differentiation. These findings suggest that age-dependent HBV chronicity is attributed to IFN-β-Axl immune regulation, which is selectively induced in young mice by excessive IFN-α/β production at early stage of HBV infection.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Miao-Tzu
authors.initials: MT
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Lu
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jian-Jhih
authors.initials: JJ
authors.lastname: Huang
authors.affiliation: National Applied Research Laboratories, National Laboratory Animal Center, Taipei, Taiwan.
authors.forename: Hsiao-Li
authors.initials: HL
authors.lastname: Chuang
authors.affiliation: National Applied Research Laboratories, National Laboratory Animal Center, Taipei, Taiwan.
authors.forename: Yen-Te
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jau-Haw
authors.initials: JH
authors.lastname: Horng
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, PROC.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, PROC.
authors.forename: Dai-Shu
authors.initials: DS
authors.lastname: Han
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chiaho
authors.initials: C
authors.lastname: Shih
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006509:Hepatitis B / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016898:Interferon-alpha; D011518:Proto-Oncogene Proteins; D016753:Interleukin-10; D016899:Interferon-beta; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase
keywords: Axl receptor tyrosine kinase; TAM receptor tyrosine kinase; hepatitis B virus (HBV); immune regulation; type I interferons