Exosomal IFITM2 transmitted to DCs inhibits IFNα pathway activation and blocks anti‐HBV efficacy of exogenous IFNα

Abstract

The negative regulators in the interferon signaling pathway inhibit intrahepatic immune response, resulting in suboptimal therapeutic response to interferon‐α treatment in chronic hepatitis B (CHB) patients. Identifying the key negative factors and elucidating the regulating mechanism are essential for improving anti‐HBV efficacy of interferon‐α. From the GEO database, we downloaded and analyzed gene expression profiles of CHB patients with different responses to interferon‐α (GSE54747), and found that innate immune status was associated with the interferon‐α‐based therapeutic response in CHB patients. Through PCR array, we found higher baseline level of interferon induced transmembrane protein 2 (IFITM2) mRNA and lower baseline level of interferon‐α mRNA in PBMCs of CHB patients with suboptimal response to interferon‐α treatment. Increased IFITM2 protein was also found in the serum of interferon‐α non‐responsive patients. With further experiments, we found that overexpressing IFITM2 in Huh7 cells suppressed endogenous interferon‐α synthesis by inhibiting phosphorylation of ERK, TBK1 and IRF3; knocking out IFITM2 enhanced the activation of endogenous interferon‐α synthesis pathway, exhibiting better inhibition on HBV replication. We also found that IFITM2 protein was shuttled via exosomes to dendritic cells, the main source of endogenous interferon‐α. Exosome‐mediated transport of IFITM2 inhibited the synthesis of endogenous interferon‐α in dendritic cells whereas the inhibitory effect was abolished when IFITM2 was knocked out. Furthermore, we demonstrated that both palmitoylation inhibitor and mutation on 70/71 sites of IFITM2 protein influenced its incorporation into exosomes. Mutated IFITM2 protein increased the effect of interferon‐α against HBV.

Conclusion

Exosome‐mediated transport of IFITM2 to dendritic cells inhibits interferon‐α pathway activation and blocks anti‐HBV efficacy of exogenous interferon‐α. The findings provide an explanation to the suboptimal response of CHB patients to interferon‐α treatment.

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