Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi 710032, China.
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
Sci Transl Med. 2019 Sep 25;11(511). doi: 10.1126/scitranslmed.aav7561.
Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to CD8 T cell-mediated cytotoxic responses through MHC class I induction in a coculture model. We show that this process is dependent on Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1), but not JAK1 or STAT2 signaling. Last, using drug prediction algorithms, we identify JAK inhibitors as promising therapeutic agents in LP and demonstrate that the JAK1/2 inhibitor baricitinib fully protects keratinocytes against cell-mediated cytotoxic responses in vitro. 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 to limit cell-mediated cytotoxicity in patients with LP.
扁平苔藓（LP）是一种病因不明的慢性消耗性炎症性疾病，影响皮肤、指甲和粘膜，目前尚无 FDA 批准的治疗方法。其组织学特征为 T 细胞和表皮角质形成细胞凋亡的密集浸润。通过对患者皮肤样本的全转录组谱分析，我们证明 LP 的特征是 II 型干扰素（IFN）炎症反应。在共培养模型中，II 型 IFN IFN-γ 被证明通过 MHC Ⅰ类诱导使角质形成细胞致敏，并增加其对 CD8 T 细胞介导的细胞毒性反应的易感性。我们表明，这个过程依赖于 Janus 激酶 2（JAK2）和信号转导和转录激活因子 1（STAT1），但不依赖于 JAK1 或 STAT2 信号。最后，我们使用药物预测算法，确定 JAK 抑制剂是 LP 有前途的治疗药物，并证明 JAK1/2 抑制剂巴瑞替尼可完全保护角质形成细胞免受体外细胞介导的细胞毒性反应。总之，这项工作阐明了 IFN-γ 在 LP 发病机制中的作用和机制，并为使用 JAK 抑制剂治疗 LP 患者以限制细胞介导的细胞毒性提供了证据。
