Assistant Professor Geisel Sch. of Med. at Dartmouth, United States
Introduction/Rationale: Ultraviolet (UV) light induces type I interferons (IFN-I) that aid repair but drive pathology when excessive, as in lupus (SLE). Loss of VISTA heightens UV-triggered IFN-I response and skin injury. Here we define how keratinocyte VISTA shapes epidermal responses to UV.
Methods: RNAseq was performed on biopsies from healthy and SLE skin pre- and 24hr after UV. GSE186476 dataset was analyzed for VSIR expression and IFN-I response in human keratinocytes. FLEX scRNA-seq was performed from skin FFPE sections from K14creVsirfl/fl and controls at baseline and 24 hr after UVB (250mJ/cm2). Human VISTA expressing mice were treated i.d. with 200ug aVISTA or control IgG immediately after UV.
Results: In human skin, VSIR expression is lower in SLE vs healthy skin 24 h after UV, coincident with heightened IFN-I activity. VSIR levels are also diminished in SLE keratinocytes at baseline, particularly in activated basal cells. In mice, scRNA-seq revealed decreased follicular and expanded basal keratinocytes in K14creVsirfl/fl skin and increased IFN-I signatures in these subsets. Both keratinocyte subsets upregulated Vsir after UV. In the absence of keratinocyte VISTA, K14creVsirfl/fl epidermis showed expansion of activated basal cells, loss of follicular keratinocytes, and further elevation in IFN-I scores. IFN-I and chemokine pathways were enriched in VISTA-deficient keratinocytes, while wound-healing programs were suppressed. UV-exposed K14creVsirfl/fl skin displayed fibroblast and monocyte expansion with melanocyte loss and high IFN-I scores in fibroblasts, macrophages, and monocytes. Cell–cell communication analysis indicated reduced junctional contacts ( JAM) and increased secreted cues (CCL, ANGPTL). Targeting VISTA reduced UV-induced ISGs and prevented skin injury.
Conclusion: Keratinocyte VISTA constrains skin IFN-I and preserves immune–stromal homeostasis after UV. Modulating VISTA locally suppresses UV-triggered IFN-I, implicating it as a novel target in inflammatory skin disease such as lupus.
