Type I interferons dominate cutaneous lichen planus inflammatory landscape driving the interface dermatitis reaction.

Cutaneous lichen planus (LP) is a chronic inflammatory skin disease histologically characterized by an interface dermatitis with lymphocyte infiltration and keratinocyte cell-death. Previous studies suggest that LP inflammation is dominated by a type I immune response involving IFN-g but its pathogenesis remains not fully elucidated yet. To investigate the inflammatory mechanisms underlying LP, we performed single-cell RNA sequencing on LP compared with healthy control skins. We demonstrate that lesional skin from patient with LP is imprinted by a type I interferon (IFN-I)-rich environment, involving all the main skin cell components. While all immune cells are imbued with this interferon signature, we highlight unique subsets of inflammatory keratinocytes and fibroblasts highly influenced by IFN-I near the epidermis-dermis junction. We also show a unique CD8+CXCL13+ T cell population exhibiting cytotoxic and epidermis-homing markers together with an enrichment in inflammatory CD16+ myeloid cells in LP skin. Herein, we illustrate that IFN-I education on all major skin cell types and particularly in keratinocytes drives the interface dermatitis reaction, thus orchestrating the cross-talk between immune and stromal cells in LP skin. Last, we suggest the effectiveness of targeting the common IFN-I receptor, IFNAR1, to switch off the activation of inflammatory pathways in an ex-vivo model of LP skin and in on patient with lupus lichen skin lesions. Together, our data provide a comprehensive characterization of LP immunopathogenesis and demonstrate the strong involvement of IFN-I in its inflammatory landscape, providing arguments for the therapeutic use of drugs targeting IFN-I pathway in patients with LP. A skin biopsy from one patient with active lichen planus was cut in half and cultured with either anti-IFNAR1 antibody (anifrolumab, 10 mm/ml AstraZeneca) or control isotype (IgG1 kappa, abcam) in RPMI enriched medium (10% FCS with 60UI/ml of IL2) for 72 hours. 3 healthy control skins from plastic surgery waste were cultured in the same condition without antibody. After 72h culture RNA was extracted for microarray analysis.