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 signaling in vivo leaded 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 to in vitro inhibition 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.
Highlights
Hepatitis B virus (HBV) infection is still a severe public health problem, with ∼350 million infections all over the world (Bitton Alaluf and Shlomai, 2016)
Activation of Notch counteracted with Epstein-Barr virus (EBV) nuclear antigen 2 to inhibit the transcription of key protein in EBV proteins production and the entry of EBV into lytic cycle (Rowe et al, 2014)
Repression of Notch receptors mediated the regulation of immune response in chronic hepatitis B (CHB) patients and the progression to end-stage liver diseases (Trehanpati et al, 2012)
Summary
Hepatitis B virus (HBV) infection is still a severe public health problem, with ∼350 million infections all over the world (Bitton Alaluf and Shlomai, 2016). It is well accepted that clinical outcome of HBV infection results from the complicated interaction. Notch-IL-22 Axis in HBV Infection between virus and host immune response (Bertoletti and Ferrari, 2016; Maini and Gehring, 2016), leading to different disease phases (Lok, 2016). HBV infection induces a series of inflammation networks, which manifested as the elevation of specific immune cell populations and molecules (Chang and Lewin, 2007). We previously screened the expression profile of cytokines and chemokines in CHB patients (Lian et al, 2014), and demonstrated the predominate proinflammatory role of interleukin (IL)-22 in HBV infection (Zhang et al, 2011)
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