Department of Dermatology and.
Department of Genetics and Development, Columbia University, Vagelos College of Physicians and Surgeons, New York, New York, USA.
JCI Insight. 2021 Apr 8;6(7):142205. doi: 10.1172/jci.insight.142205.
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) are key intracellular mediators in the signal transduction of many cytokines and growth factors. Common γ chain cytokines and interferon-γ that use the JAK/STAT pathway to induce biological responses have been implicated in the pathogenesis of alopecia areata (AA), a T cell-mediated autoimmune disease of the hair follicle. We previously showed that therapeutic targeting of JAK/STAT pathways using the first-generation JAK1/2 inhibitor, ruxolitinib, and the pan-JAK inhibitor, tofacitinib, was highly effective in the treatment of human AA, as well as prevention and reversal of AA in the C3H/HeJ mouse model. To better define the role of individual JAKs in the pathogenesis of AA, in this study, we tested and compared the efficacy of several next-generation JAK-selective inhibitors in the C3H/HeJ mouse model of AA, using both systemic and topical delivery. We found that JAK1-selective inhibitors as well as JAK3-selective inhibitors robustly induced hair regrowth and decreased AA-associated inflammation, whereas several JAK2-selective inhibitors failed to restore hair growth in treated C3H/HeJ mice with AA. Unlike JAK1, which is broadly expressed in many tissues, JAK3 expression is largely restricted to hematopoietic cells. Our study demonstrates inhibiting JAK3 signaling is sufficient to prevent and reverse disease in the preclinical model of AA.
Janus 激酶/信号转导子和转录激活子（JAK/STAT）是许多细胞因子和生长因子信号转导的关键细胞内介质。共同 γ 链细胞因子和干扰素-γ利用 JAK/STAT 途径诱导生物学反应，与斑秃（AA）的发病机制有关，AA 是一种毛囊 T 细胞介导的自身免疫性疾病。我们之前表明，使用第一代 JAK1/2 抑制剂鲁索利替尼和泛 JAK 抑制剂托法替尼靶向 JAK/STAT 途径的治疗在治疗人类 AA 以及预防和逆转 C3H/HeJ 小鼠模型中的 AA 方面非常有效。为了更好地定义个体 JAK 在 AA 发病机制中的作用，在这项研究中，我们使用全身性和局部递送方法，在 C3H/HeJ 小鼠 AA 模型中测试和比较了几种下一代 JAK 选择性抑制剂的疗效。我们发现 JAK1 选择性抑制剂和 JAK3 选择性抑制剂均可强力诱导毛发再生并减少 AA 相关炎症，而几种 JAK2 选择性抑制剂未能恢复患有 AA 的 C3H/HeJ 小鼠的毛发生长。与广泛表达于许多组织中的 JAK1 不同，JAK3 的表达主要局限于造血细胞。我们的研究表明，抑制 JAK3 信号足以预防和逆转 AA 的临床前模型中的疾病。
