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
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 7 (04 08 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 33830087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Azetidines
• CEP 33779
• Cytokines
• INCB039110
• Isonicotinic Acids
• Klrk1 protein, mouse
• NK Cell Lectin-Like Receptor Subfamily K
• Nitriles
• PF-06651600
• Piperidines
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• Pyrimidines
• Pyrroles
• Triazoles
• ruxolitinib
• tofacitinib
• Jak1 protein, mouse
• Jak2 protein, mouse
• Jak3 protein, mouse
• Janus Kinase 1
• Janus Kinase 2
• Janus Kinase 3

Topics

• Administration, Topical
• Alopecia Areata (drug therapy, metabolism, prevention & control)
• Animals
• Azetidines (administration & dosage, pharmacology)
• CD8-Positive T-Lymphocytes (drug effects, metabolism)
• Cytokines (metabolism)
• Isonicotinic Acids (administration & dosage, pharmacology)
• Janus Kinase 1 (antagonists & inhibitors, metabolism)
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Janus Kinase 3 (antagonists & inhibitors, metabolism)
• Macrophages (drug effects, metabolism)
• Mice, Inbred C3H
• NK Cell Lectin-Like Receptor Subfamily K (metabolism)
• Nitriles (pharmacology)
• Piperidines (pharmacology)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Pyrroles (administration & dosage, pharmacology)
• Triazoles (pharmacology)
• Mice