Ultraviolet B Irradiation Causes Stimulator of Interferon Genes-Dependent Production of Protective Type I Interferon in Mouse Skin by Recruited Inflammatory Monocytes.

Abstract

Photosensitivity is common in patients with systemic lupus erythematosus, although the mechanisms linking ultraviolet (UV) light to flares are not well understood. We undertook this study to determine whether repetitive UVB exposure could induce type I interferon (IFN) production in normal mouse skin, and to investigate the roles of inflammatory monocytes and plasmacytoid dendritic cells (PDCs) in type I IFN production and development of UVB irradiation-induced inflammation. Mice were irradiated with UVB at 100 mJ/cm2 for 5 days, and cutaneous manifestations were examined by messenger RNA expression of inflammatory and type I IFN response genes, histology, and flow cytometry. Inflammatory monocyte and PDC depletion experiments were performed in CCR2-diphtheria toxin receptor (DTR)-transgenic mice and blood dendritic cell antigen 2-DTR-transgenic mice. The roles of type I IFN and of the adaptor protein stimulator of IFN genes (STING) in UVB irradiation-induced inflammation were investigated using IFN-α/β/ω receptor (IFNAR)-knockout mice and STING-knockout mice. Repeated UVB irradiation stimulated an inflammatory cell infiltrate and induction of type I IFN and proinflammatory cytokines. Interestingly, the type I IFN response was independent of PDCs but dependent on inflammatory monocytes, which were recruited following UVB irradiation. The adaptor protein STING was necessary for both type I IFN and proinflammatory cytokine expression in the skin. UVB-irradiated IFNAR-knockout mice showed increased levels of proinflammatory genes and more severe inflammation by histology, suggesting a protective role for type I IFN. In wild-type mice, repeated doses of UVB irradiation induce monocyte-dependent and PDC-independent expression of type I IFN together with expression of other proinflammatory cytokines. Induction is dependent on the adaptor protein STING. Surprisingly, studies using IFNAR-deficient mice revealed that type I IFN protects against UVB irradiation-induced skin inflammation, in part by attenuating proinflammatory cytokine expression and limiting tissue damage.