Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata
Zhenpeng Dai, … , Yuqian Chang, Angela M. Christiano
Zhenpeng Dai, … , Yuqian Chang, Angela M. Christiano
Published April 8, 2021
Citation Information: JCI Insight. 2021;6(7):e142205. https://doi.org/10.1172/jci.insight.142205.
View: Text | PDF
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

×

Figure 5

Reversal of AA with topical JAK1- or JAK3-selective inhibitor treatment.

Options: View larger image (or click on image) Download as PowerPoint
Reversal of AA with topical JAK1- or JAK3-selective inhibitor treatment....
C3H/HeJ mice with long standing AA were treated topically with INCB039110 (JAK1i), CEP-33779 (JAK2i), or PF-06651600 (JAK3i) or control daily for 12 weeks, in cohorts of 4 mice per group. (A) Representative images of individual JAK inhibitor– or vehicle-treated C3H/HeJ mice before or after 12 weeks’ treatment. (B) Percentage of dorsal hair loss or regrowth is 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 < 0.05, ***P < 0.001 (unpaired Student’s t test). (C) Representative immunofluorescence images of skin sections from JAKi- or vehicle-treated mice, stained with anti-CD8, anti–MHC class I, or anti–MHC class II mAbs. Scale bar: 100 μm. (D) Percentages of skin infiltrating CD45+ leukocytes, NKG2D+CD8+ T cells, CD44+CD62L–CD8+ T cells, CD103+CD69+CD8+ T cells, IFN-γ–producing CD8+ T cells, as well as GZMB- or PRF1-producing CD8+ T cells within indicated populations within the skin after JAK inhibitor treatment. *P < 0.05, **P < 0.01, ***P < 0.001 (1-way ANOVA). Two replicate experiments were performed for a total of 8 mice per group.