IRF6 Enhances IFN-β Expression and Inhibits Viral Replication to Reduce the Severity of Herpetic Stromal Keratitis.

Abstract

Purpose: Herpes simplex virus type 1 (HSV-1) infection of the human eye can lead to herpes simplex keratitis, which is the leading cause of infectious blindness worldwide. Inflammation invading the corneal stroma causes herpetic stromal keratitis (HSK). Interferon regulatory factor 6 (IRF6) is a member of the interferon regulatory factor family and is involved in the antiviral response against human papillomavirus 16. However, the mechanism related to the involvement of IRF6 in the host anti-HSV-1 response is unclear, and how latent infection and viral reactivation trigger corneal stromal inflammation remains unknown. Therefore, we investigated the role of IRF6 in HSV-1 infection.

Methods: Proteomic detection techniques indicated that IRF6 was expressed at low levels in the corneas of HSK model mice. The antiviral effects of IRF6 have been demonstrated in animal and cellular studies. HSV-1 replication was activated when IRF6 was silenced in human corneal epithelial cells (HCECs), and IRF6 overexpression inhibited viral replication. HSK was established after locally inoculating mouse corneas with lentivirus to overexpress IRF6.

Results: The degree of inflammation was attenuated, and proinflammatory cytokine secretion was reduced in the mice overexpressing IRF6 compared with that in the lentivirus control mice, suggesting that IRF6 attenuates the severity of HSK. Silencing of protein kinase C delta and receptor-interacting serine/threonine kinase 4 reduced IRF6 phosphorylation and inhibited its degradation during HCEC infection with HSV-1.

Conclusion: These findings indicate that IRF6 is involved in the immune response against HSV-1 virus, and IRF6 can be used as a therapeutic target for treating HSK.