FTY720 alleviates HBV-mediated inflammatory liver injury through a dual role of inhibiting lymphocyte trafficking and viral replication.

BACKGROUND

The host immune response plays a critical role in clearing hepatitis B virus infection. However, in chronic hepatitis B, this response fails to eliminate the virus, leading to recurrent inflammation, liver tissue damage, and a gradual progression from hepatitis to fibrosis, and eventually, hepatocellular carcinoma. Reducing liver injury while enhancing antiviral efficacy remains a key objective in hepatitis B virus treatment development. Our previous research revealed a close association between hepatitis B virus infection and the sphingosine 1-phosphate signaling pathway. Consequently, this study aims to explore the dual role of FTY720, an immune modulator that targets sphingosine- 1-phosphate receptor, in hepatitis B virus-related liver injury.

METHODS

In this study, The peripheral blood leukocyte count and the expression of sphingosine 1-phosphate receptor on lymphocytes were compared between chronic hepatitis B patients and healthy controls. In vitro experiments were conducted to evaluate the direct antiviral effects of FTY720 on two hepatitis B virus models: HepG2.2.15 and Huh7 cells transfected with pUC19-HBV1.3. Additionally, the study investigated the influence of FTY720 on the chemotaxis of peripheral blood mononuclear cells induced by the supernatant of hepatitis B virus-infected HepG2-NTCP cells. An in vivo model using hepatitis B virus hyperbaric hydrodynamic injection in mice was also employed to assess the impact of FTY720 on both HBV replication and hepatic lymphocyte infiltration.

RESULTS

Peripheral blood lymphocyte counts were reduced, while sphingosine 1-phosphate receptor expression was elevated in chronic hepatitis B patients compared to healthy controls. Simultaneously, antiviral therapy solely utilizing nucleotide analogues could not fully restore the peripheral blood lymphocyte count in patients with chronic hepatitis B. In vitro, FTY720 effectively inhibited hepatitis B virus replication in two models: HepG2.2.15 cells containing hepatitis B virus virions and pUC19-HBV1.3-transfected Huh7 cells. Furthermore, supernatants from hepatitis B virus-infected HepG2-NTCP cells induced increased lymphocyte chemotaxis, which was suppressed by FTY720. In a hepatitis B virus mouse model, FTY720 significantly reduced viral DNA and protein levels, while also decreasing inflammatory hepatocyte necrosis, liver lymphocyte infiltration, and sphingosine 1-phosphate receptor expression on circulating lymphocytes.

CONCLUSIONS

These findings suggest that FTY720 can inhibit both hepatitis B virus replication and hepatitis B virus-related liver damage by modulating lymphocyte migration. Further investigation into the specific mechanisms underlying the interaction between FTY720 and hepatitis B virus is warranted.