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

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. Overall design: Immortalized primary human keratinocytes (N/TERT) in culture were treated for 24 hours with 3 differents subtypes of interferons and their gene expression prolifing were studied using microarray.

扁平苔藓（Cutaneous lichen planus, LP）是一种慢性炎症性皮肤病，组织学特征为界面性皮炎伴淋巴细胞浸润及角质形成细胞死亡。既往研究表明，LP的炎症以涉及干扰素γ（IFN-γ）的I型免疫应答为主，但其发病机制尚未完全阐明。为探究LP的炎症发生机制，我们对LP皮损与健康对照皮肤开展了单细胞RNA测序。本研究证实，LP患者的皮损处于富含I型干扰素（type I interferon, IFN-I）的微环境中，涵盖皮肤所有主要细胞组分。尽管所有免疫细胞均携带该干扰素特征，但我们重点揭示了位于表皮-真皮交界处、受IFN-I高度调控的独特炎症性角质形成细胞与成纤维细胞亚群。此外，我们在LP皮肤中发现了独特的CD8+CXCL13+ T细胞群，该细胞群同时表达细胞毒性及表皮归巢标志物，且炎症性CD16+髓系细胞呈现富集状态。本研究阐明，IFN-I对皮肤所有主要细胞类型（尤其是角质形成细胞）的教育作用驱动了界面性皮炎反应，进而协调了LP皮肤中免疫细胞与基质细胞的相互串扰。最后，我们在LP皮肤的离体模型及1例苔藓样狼疮皮损患者中验证，靶向通用I型干扰素受体IFNAR1可有效关闭炎症通路的激活。综上，本研究全面表征了LP的免疫发病机制，证实IFN-I在其炎症谱中发挥关键调控作用，为靶向IFN-I通路的药物应用于LP患者提供了理论支撑。总体实验设计：将永生化原代人角质形成细胞（N/TERT）体外培养后，采用3种不同亚型的干扰素处理24小时，通过微阵列技术分析其基因表达谱。