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

Abstract

Objective 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. Methods 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. Results 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. Conclusion 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.

The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent

“…Consistent with activation of the cGAS-STING pathway and failure to detect pDC in short term experiments (Sontheimer et al, 2017) and confirmed here (not shown), exposure to UVB light triggered an early increase in the circulating levels of IFNβ in WT mice ( Fig. 3D).…”

“…How photosensitivity leads to systemic disease exacerbations in SLE is unknown. We previously showed that repetitive exposure of mice to low doses (100 mJ/cm 2 ) of UVB light triggered IFN-I response in the skin (Sontheimer et al, 2017), a result recently confirmed by Wolf et al . However, we observed that expression of type I interferon (IFN-I) signature genes (ISG) in the skin was blunted in mice deficient in the DNA sensing adapter, STING (stimulator of interferon genes) (Sontheimer et al, 2017).…”

“…We previously showed that repetitive exposure of mice to low doses (100 mJ/cm 2 ) of UVB light triggered IFN-I response in the skin (Sontheimer et al, 2017), a result recently confirmed by Wolf et al . However, we observed that expression of type I interferon (IFN-I) signature genes (ISG) in the skin was blunted in mice deficient in the DNA sensing adapter, STING (stimulator of interferon genes) (Sontheimer et al, 2017). Since cGAS is the most prominent DNA sensor leading to STING activation and this pathway is activated following UV light exposure of cells in vitro and gamma irradiation in vivo (Deng et al, 2014;Kemp et al, 2015;Vanpouille-Box et al, 2017), we addressed whether cGAS was necessary for the in vivo IFN-I response to UV light.…”

“…In vitro and ex vivo studies reported that UVB and UVC light-mediated cell damage induced IFN-I in keratinocytes and other cell types (Gehrke et al, 2013;Sarkar et al, 2018), possibly aided by the downregulation of ULK-1, a STING inhibitor (Kemp et al, 2015). We and others observed that repeated exposure to low doses of UVB light (100mJ/cm 2 per day for 5 days) caused a modest upregulation in ISG expression in the skin of normal mice (Sontheimer et al, 2017;Wolf et al, 2019). However, this subacute model generates cycles of inflammation and resolution, which complicates understanding as to whether IFN-I reflects immediate injury or a wound repair response.…”

“…UV light is genotoxic, cytotoxic, and generates modified nucleic acids such as oxidized DNA (Gehrke et al, 2013). Recently, we discovered that IFN-I and inflammatory cytokines induced by UVB light were markedly reduced in STING deficient mice (Sontheimer et al, 2017). Canonically, STING has been thought to act primarily as a cytosolic DNA sensing adaptor protein downstream of cGAS.…”