503 IL-36β renders keratinocytes resistant to herpes simplex virus-1 through interferon response factor-1 (IRF1) dependent and independent pathways

Abstract

The IL-36 cytokines are associated with inflammation in psoriasis and bacterial infections. Recent work has suggested that the IL-36 cytokines also protect against viral infections; however, the mechanism of action has remained unknown. We here report a novel pathway whereby IL-36 promotes innate antiviral immunity in both mouse and human models of herpes simplex virus-1 (HSV-1) infections. Specifically, we find that IL-36β deficient mice poorly restrict viral replication in skin keratinocytes and have diminished expression of the antiviral protein Mx1. Mouse and human keratinocytes exposed in vitro to IL-36β restrict viral replication better than control cells. IL-36β also promotes expression of Mx1 during HSV-1 infection. CRISPR/Cas9 gene editing of the interferon response factor-1 gene IRF1 in human keratinocytes revealed that both the IL-36β induced Mx1 expression and antiviral state are dependent upon IRF1. Interestingly, while in mouse primary keratinocytes IL-36β induced Mx1 expression is IRF1 dependent, the IL-36β initiated antiviral state is independent of IRF1. In vivo in mice IRF1 is required for preventing disseminated disease, but is dispensable for restricting viral replication within the skin. Hence, the involvement of IRF1 in human and mouse innate immunity within keratinocytes has diverged during evolution; this could represent a gain-of-function in humans or a loss-of-function in mice. Overall, IL-36β promotes innate antiviral immunity in keratinocytes in IRF1 dependent and independent manners.