Session Type: Plenary Session II
Session Time: 11:00AM-12:30PM
Background/Purpose: Interferon response genes (ISG) are strongly expressed in the skin of many patients with systemic lupus erythematosus (SLE). Since plasmacytoid dendritic cells (pDC) are also found in the skin of SLE patients with rashes, it is assumed that type I Interferon (IFN-I) activation in the skin is caused by immune complex activation of pDC. We previously showed that UV responses were blunted in mice deficient in the DNA sensing adapter protein STING. Since cyclic cGAS acting upstream of STING is implicated in Aicardi Goutieres Syndrome patients with skin manifestations, and a proportion of SLE patients have elevated cGAMP in their blood, we examined the role of cGAS in UVB light mediated skin injury.
Methods: Mice (B6 female (f) and male (m), B6.cGAS-/- f, and B6.Ifnar-/- f, 3-4mo) were exposed to a single dose of UVBL (500mJ/cm2). Blood draws and skin biopsies were performed prior to and at different times after UVB light injury. For experiments looking at non-lesional ISG expression, mice were irradiated along one half of the back (UVB) while the other half was shielded from exposure (non-UVB). Biopsies in the non-UVB region were performed ~0.5 cm away from the UVB area. ISG (Mx1, Isg15, Isg20, Ifit1, Ifit3, Irf7, Ifi44) and inflammatory genes (TNFα, Il6, Il1β) transcripts were quantified by QPCR and normalized to 18s.
Results: A single high dose of UVB light triggered rapid (6hr) and sustained (48hr) cutaneous ISG expression in B6 mice (~10 fold increase), with significantly greater early ISG upregulation in female mice compared to their age-matched male counterparts. Local cutaneous IFN-I response was accompanied by early (6hr) increase in circulating IFNβ protein levels and upregulation in ISG expression in the peripheral blood cells. Female mice deficient in cGAS showed no ISG expression in the skin 6hr after UVB light exposure, while ISG expression at 24hr, though present, was significantly lower than in the B6 controls (45.7% – 84.1% less). ISG expression in peripheral blood cells was also significantly reduced in the absence of cGAS. In contrast to ISG, rapid gene expression of inflammatory cytokines TNFα, IL6, and IL1β (6hr) in the skin following acute UVB light exposure was not impacted by the loss of cGAS. Of note, ISG expression in non-lesional skin covered during irradiation was detected at 6 and 24hr after injury. The ISG expression in non-lesional skin was cGAS-dependent at 6hr and partially at 24hr after UVB light injury.
Conclusion: Acute skin exposure to UVB light triggers rapid and sustained ISG expression in both skin and blood. The early cutaneous response is higher in the females and is cGAS dependent, while blood ISG expression is partially dependent on cGAS. The requirement for cGAS in UVB light-mediated IFN-I response in the skin is temporally regulated: i) cGAS is required for early (6hr after UV) ISG expression and ii) cGAS contributes to, but is not the sole player in late (24hr after UV) ISG induction. Presence of IFN-I signature in both the non-lesional skin as well as in peripheral blood cells, together with increased circulating IFNβ levels, provide a model by which skin exposure to UVB light drives systemic activation of the IFN-I response.
To cite this abstract in AMA style:Skopelja-Gardner S, An J, Sun X, Tanaka L, Tai J, Hermanson P, Kawasumi M, Elkon K. UV Light Induces Acute Type I Interferon Production in the Skin and Blood Which Is cGAS Dependent [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/uv-light-induces-acute-type-i-interferon-production-in-the-skin-and-blood-which-is-cgas-dependent/. Accessed December 2, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/uv-light-induces-acute-type-i-interferon-production-in-the-skin-and-blood-which-is-cgas-dependent/