title: Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection.
abstract: The mechanism of hepatitis B virus (HBV) induced liver inflammation is not fully elucidated. Notch signaling augmented interleukin (IL)-22 secretion in CD4+T cells, and Notch-IL-22 axis fine-tuned inflammatory response. We previously demonstrated a proinflammatory role of IL-22 in HBV infection. Thus, in this study, we analyzed the role of Notch in development of IL-22-producing cells in HBV infection by inhibition of Notch signaling using γ-secretase inhibitor DAPT in both hydrodynamic induced HBV-infected mouse model and in peripheral blood cells isolated from patients with HBV infection. mRNA expressions of Notch1 and Notch2 were significantly increased in livers and CD4+T cells upon HBV infection. Inhibition of Notch signalingin vivoleaded to the reduction in NKp46+innate lymphoid cells 22 (ILC22) and lymphoid tissue inducer 4 (LTi4) cells in the liver. This process was accompanied by downregulating the expressions of IL-22 and related proinflammatory cytokines and chemokines in the liver, as well as blocking the recruitment of antigen-non-specific inflammatory cells into the liver and subsequent liver injury, but did not affect HBV antigens production and IL-22 secretion in the serum. Furthermore, IL-22 production in HBV non-specific cultured CD4+T cells, but not HBV-specific CD4+T cells, was reduced in response toin vitroinhibition of Notch signaling. In conclusion, Notch siganling appears to be an important mediator of the liver inflammation by modulating hepatic ILC22. The potential proinflammatory effect of Notch-mediated ILC22 may be significant for the development of new therapeutic approaches for treatment of hepatitis B.
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Xin
authors: X
authors: Wei
authors: Department of Infectious Diseases, Xijing Hospital, Fourth Military Medical University Xi'an, China.
authors: Jiu-Ping
authors: JP
authors: Wang
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Chun-Qiu
authors: CQ
authors: Hao
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Xiao-Fei
authors: XF
authors: Yang
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Lin-Xu
authors: LX
authors: Wang
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Chang-Xing
authors: CX
authors: Huang
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Xue-Fan
authors: XF
authors: Bai
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Jian-Qi
authors: JQ
authors: Lian
authors: Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
authors: Ye
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006509:Hepatitis B / Q000473:pathology*; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D051379:Mice; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism*; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000097043:Interleukin-22
keywords: Notch signaling; hepatitis B virus; inflammation; innate lymphoid cells; interleukin-22