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.
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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 1

Inhibition of cytokine-dependent signaling by JAK-selective inhibitors.

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Inhibition of cytokine-dependent signaling by JAK-selective inhibitors. ...
(A–E) C3H/HeJ mouse splenocytes were pretreated with 1 μM of INCB039110 (JAK1i), CEP-33779 (JAK2i), or PF-06651600 (JAK3i) or vehicle control for 1 hour at 37°C. The treated cells were stimulated with IL-7 (20 ng/mL), IL-15 (40 ng/mL), IL-10 (50 ng/mL), GM-CSF (50 ng/mL), or IFN-γ (50 ng/mL) for 20 minutes at 37°C. Phosphorylated STAT (p-STAT) expression in indicated cell subsets was presented as representative plots and mean fluorescence intensity (MFI). CD3+CD8+ cells (A and B), CD19+ cells (C), CD11b+ cells (D), and CD3+ cells (E) were gated for p-STAT expression. (F) C3H/HeJ mouse HF dermal sheath cells were pretreated with 1 μM of INCB039110, CEP-33779, or vehicle control for 1 hour at 37°C. The treated cells were then stimulated with IFN-γ (50 ng/mL) for indicated time points at 37°C and analyzed by Western blotting for p-STAT1, total STAT1, and the housekeeping protein β-actin. (G and H) C3H/HeJ mouse splenocytes were pretreated with 500 nM of indicated JAKi or vehicle control for 1 hour at 37°C. The treated cells from C3H/HeJ mice were then stimulated with 20 ng/mL IL-15 and 250 nM of indicated JAKi at 37°C for 72 hours. (G) Expression of NKG2D and (H) expression of Granzyme B (GZMB) and Perforin 1 (PRF1) by CD8+ T cells presented as representative plots and MFI. The data shown are from 1 representative experiment out of 2 replicates. W/O, without treatment.