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.
Highlights
Alopecia areata (AA) is an autoimmune disease of the hair follicle (HF) that ranges in presentation from circular patches on the scalp to complete hair loss and is associated with an enormous psychological burden to patients [1, 2]
We previously showed that cytotoxic natural killer group 2 member D–positive (NKG2D+), CD8+ T cells accumulate in the skin and contribute to HF destruction [4, 5]
We found that numbers and frequencies of total CD8+ T cells, CD8+NKG2D+ T cells, and CD8+ TE/M cells within the skin draining lymph nodes (SDLNs) were not significantly changed by any of the JAK-selective inhibitors compared with control mice (Supplemental Figure 11), suggesting that systemic absorption of topically applied JAK inhibitors was minimal
Summary
Alopecia areata (AA) is an autoimmune disease of the hair follicle (HF) that ranges in presentation from circular patches on the scalp to complete hair loss and is associated with an enormous psychological burden to patients [1, 2]. The pathogenesis of AA is associated with the overexpression of proinflammatory cytokines, such as interferon-γ (IFN-γ) and common γ chain (γc) cytokines, which break down HF immune privilege and promote the survival and function of cytotoxic T lymphocytes in affected skin [6, 7]. These proinflammatory cytokines signal through their receptors via the family of Janus kinase/signal transducers and activators of transcription (JAK/STAT). The relative contribution of JAK1, JAK2, and JAK3 inhibition to the therapeutic benefit of ruxolitinib, baricitinib, and tofacitinib in AA has not been investigated
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