Background/Purpose: Persistent production of type I interferons (IFN-Is) is one of the hallmarks of cutaneous lupus erythematosus (CLE) that is exacerbated by ultraviolet (UV) light. Though photosensitivity affects >80% of CLE patients, no therapies address this disease manifestation. Here we demonstrate that decreased VISTA (Vsir) expression, also observed in human lupus non-lesional skin, creates a CLE-like skin environment sensitive to UV light, at least in part due to STING-mediated IFN-I signaling.

Methods: Skin biopsies from B6, B6.Vsir-/- (VISTA-deficient), B6.Vsir-/-Sting-/-, KRT14creVsirfl/fl (Vsir-/- in keratinocytes), and cre-Vsirfl/fl female mice (3 mo) were collected prior to and 48 hr after UVB (500mJ/cm² one dose). Gene expression was quantified by RNA-seq. Skin infiltrating cells were quantified by flow cytometry and GSVA analysis of RNAseq data. Sc-RNAsq data from GSE186476 was reanalyzed using the Seurat package for Vsir and IFN-I score expression. Cutaneous Lupus disease activity and severity (CLASI) score was calculated as the sum of scores for mouse ears, upper and lower backs for erythema, scaling and scarring. IFN-I score derived as the sum of 6 IFN-stimulated gene (ISGs) normalized expression relative to 18s by qPCR.

Results: At homeostasis, IFN-I signaling and IFNk expression are highly upregulated in B6.Vsir-/-, compared to wild-type (wt, B6) skin, despite the absence of spontaneous skin lesions. Vsir deficiency in keratinocytes only is sufficient to drive the increased IFN-I signaling in the skin. Of relevance to human disease, analysis of skin scRNAseq data revealed lower Vsir expression in non-lesional CLE compared to healthy skin. This was particularly notable in keratinocyte subsets with a high IFN-I signature. Analogous to the immune cell composition in human CLE skin, monocytes, pDCs, CD8 T cells, and B cells are elevated in Vsir-/- skin, while Treg are significantly decreased, compared to wt skin. Enrichment for CD8 T cells, monocytes, and B cells was also seen in the skin of KRT14^creVsir^fl/fl skin. Acute exposure to UV light results in visible skin sensitivity, marked by significantly higher CLASI score in Vsir-/- vs. wt skin 48hr after UV, accompanied by increased infiltration of inflammatory monocytes and decreased levels of Foxp3+T regulatory cells. Given the role of STING signaling in skin UV responses, we asked if the absence of Sting rescues the photosensitive skin reaction in the Vsir-/- skin. At baseline, Vsir-/-Sting-/- mice have lower skin IFN-I signature compared to Vsir-/- mice. Levels of monocytes, CD8 T cells, and Treg are restored to almost baseline wt levels. Vsir.Sting-/- mice have a reduced CLASI score after UV, accompanied by a decrease in monocyte infiltration and increase in Treg levels, compared to Vsir-/- mice.

Conclusion: These studies demonstrate that VISTA deficient skin, even when limited to keratinocytes, mimics non-lesional CLE skin in terms of inflammatory pathway signatures and immune cell composition. VISTA serves as a guardian against UV-induced damage in the skin, likely by suppressing STING-induced IFN-I production. Decreased Vsir expression in CLE non-lesional skin and IFN-I^high keratinocyte suggests clinical relevance.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/vista-deficiency-alters-the-skin-immune-cell-composition-and-confers-skin-sensitivity-to-uv-light/