Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata
Zhenpeng Dai, James Chen, Yuqian Chang, Angela M. Christiano
Zhenpeng Dai, James Chen, Yuqian Chang, Angela M. Christiano
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Research Article Inflammation

Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata

Abstract

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.

Authors

Zhenpeng Dai, James Chen, Yuqian Chang, Angela M. Christiano

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Figure 2

JAK1-selective inhibitor treatment reversed AA.

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JAK1-selective inhibitor treatment reversed AA. Five C3H/HeJ AA mice per...
Five C3H/HeJ AA mice per group were treated systemically with INCB039110 (JAK1i) or CEP-33779 (JAK2i) at a dosage of 50 mg/kg for 12 weeks. (A) Representative images of individual JAK3i or vehicle-treated C3H/HeJ mice before or after 12 weeks’ treatment. (B) Time course of hair regrowth shown as weeks after treatment. **P < 0.01, log-rank test. (C) Percentage of total skin hair loss or regrowth shown before and after treatment. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. **P < 0.01, ***P < 0.001 (unpaired Student’s t test). (D) Representative immunofluorescence images of skin sections from JAKi- or control-treated mice, stained with anti-CD8, anti–MHC class I, or anti–MHC class II mAbs. Scale bar: 200 μm. (E) and (F) Percentages of skin infiltrating CD45+ leukocytes, CD44+CD62L–CD8+ T cells, NKG2D+CD8+ T cells, as well as IFN-γ–producing CD8+ T cells within indicated populations within the skin after JAK3i treatment. *P < 0.05, ***P < 0.001 (1-way ANOVA). Two replicate experiments were performed for a total of 10 mice per group.