Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa. LP is histologically characterized by dense infiltration of T cells and epidermal keratinocyte death. However, little is known about the pathogenesis of LP, and there is urgent need for more effective treatments. Here, using global transcriptomic profiling of LP samples(n=37) and healthy controls (n=24), we demonstrate that LP is characterized by type II, but not type I, interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to cytotoxic responses. We further demonstrate that the promotion of cytotoxic responses to IFN-γ-in keratinocytes are MHC class I dependent and reliant upon JAK1/STAT1 but not JAK1 or STAT2 signaling. Thus, JAK2 or STAT1 knock-outs by CRISPR/Cas9 completely inhibit cell-mediated cytotoxic responses to IFN-γ primed keratinocytes. Lastly, using drug prediction algorithms on our transcriptomic data JAK inhibitors are identified as promising therapeutic agents in LP, which we confirm using the JAK1/2 inhibitor baricitinib, which fully protects keratinocytes against cell-mediated cytotoxic responses. In summary, this work elucidates the role and mechanisms of IFN-γ in LP pathogenesis and provides evidence for the therapeutic use of JAK-inhibitors in patients with LP.
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