Background/Purpose: Systemic lupus erythematosus (SLE) patients have a prominent type I interferon (IFN-I) signature in both the lesional and non-lesional skin. We recently showed that exposure to ultraviolet (UV) light triggers cutaneous IFN-I response, in a cGAS-dependent manner. The discovery that ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) hydrolyzes cGAMP, second messenger of the cGAS-STING DNA sensing pathway, in tumor immune responses prompted the question whether ENPP1 regulates UV light stimulated IFN-I signature in the skin. Since ENPP1 expression has been association with melanogenesis, we also investigated the role of skin pigmentation in IFN-I response and its link with ENPP1 expression.

Methods: Mice (C57BL/6J, cGAS-/-, and B6(Cg)-Tyr^c-2J/J Albino, 3mo) were exposed to one dose of UVB light (500mJ/cm²). Skin biopsies (6mm) were obtained prior to and on days 1 and 2 after UV and tissue digested with DNAse I and Liberase TM, from UV exposed and unexposed skin (< 0.5cm from exposed area) in some experiments. ENPP1 protein expression in non-immune (CD45-) and immune cells (CD45+) was determined by flow cytometry and gene expression by qPCR. Mice were treated intradermally with ENPP1 inhibitor (STF-1084, 0.1mM) or vehicle and expression of interferon stimulated genes (ISG) determined 16hr later by qPCR.

Results: Exposure to a single dose of UV light triggers ISG expression in both the UV-exposed (6hr and 24hr) and non-UV exposed skin (24hr) in B6 mice. This spreading of the IFN-I response 24hr after UV exposure was significantly lower in cGAS-deficient mice. Dermal inhibition of ENPP1, extracellular enzyme that hydrolyzes cGAMP, significantly augmented skin ISG expression after UV light exposure in B6 mice. Interestingly, we observed that ENPP1 expression, found on both CD45- and CD45+ skin cells, was markedly increased in albino CD45- but not B6 mouse skin cells after UV exposure (~60% vs. 5% positive, respectively). This differential ENPP1 response was accompanied by significantly lower ISG expression in albino compared to B6 skin, on day 1 after UV exposure. Dermal inhibition of extracellular ENPP1 in albino mice significantly increased the ISG expression in response to UV light.

Conclusion: Acute skin exposure to UV light triggers spreading of ISG expression in non-UV exposed skin, suggesting that UV light contributes to the IFN-I signature observed in non-lesional skin in SLE. The cGAS requirement for ISG spreading and augmented IFN-I response following ENPP1 inhibition, indicate that extracellular cGAMP amplifies skin ISG induction following UV exposure. The reduced ISG expression in albino compared to B6 mice is likely explained by UV induced ENPP1 expression which reduces extracellular cGAMP. Overall, these findings suggest a role for skin pigmentation in the IFN-I response to UV light that is linked to ENPP1 mediated regulation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enpp1-regulates-uv-light-triggered-type-i-interferon-response-in-the-skin/