The Effect of JAK Inhibitor on the Survival, Anagen Re-Entry, and Hair Follicle Immune Privilege Restoration in Human Dermal Papilla Cells

Abstract

Topical or systemic administration of JAK inhibitors has been shown to be a new treatment modality for severe alopecia areata (AA). Some patients show a good response to JAK inhibitors, but frequently relapse after cessation of the treatment. There have been no guidelines about the indications and use of JAK inhibitors in treating AA. The basic pathomechanism of AA and the relevant role of JAK inhibitors should support how to efficiently use JAK inhibitors. We sought to investigate the effect of JAK1/2 inhibitor on an in vitro model of AA and to examine the possible mechanisms. We used interferon gamma-pretreated human dermal papilla cells (hDPCs) as an in vitro model of AA. Ruxolitinib was administered to the hDPCs, and cell viability was assessed. The change of expression of the Wnt/β-catenin pathway, molecules related to the JAK-STAT pathway, and growth factors in ruxolitinib-treated hDPCs was also examined by reverse transcription PCR and Western blot assay. We examined immune-privilege-related molecules by immunohistochemistry in hair-follicle culture models. Ruxolitinib did not affect the cell viability of the hDPCs. Ruxolitinib activated several molecules in the Wnt/β-catenin signaling pathway, including Lef1 and β-catenin, and suppressed the transcription of DKK1 in hDPCs, but not its translation. Ruxolitinib reverted IFN-γ-induced expression of caspase-1, IL-1β, IL-15, and IL-18, and stimulated several growth factors, such as FGF7. Ruxolitinib suppressed the phosphorylation of JAK1, JAK2 and JAK3, and STAT1 and 3 compared to IFN-γ pretreated hDPCs. Ruxolitinib pretreatment showed a protective effect on IFN-γ-induced expression of MHC-class II molecules in cultured hair follicles. In conclusion, ruxolitinib modulated and reverted the interferon-induced inflammatory changes by blocking the JAK-STAT pathway in hDPCs under an AA-like environment. Ruxolitinib directly stimulated anagen-re-entry signals in hDPCs by affecting the Wnt/β-catenin pathway and promoting growth factors in hDPCs. Ruxolitinib treatment prevented IFN-γ-induced collapse of hair-follicle immune privilege.

Mesenchymal Stem Cells Antagonize IFN-Induced Proinflammatory Changes and Growth Inhibition Effects via Wnt/β-Catenin and JAK/STAT Pathway in Human Outer Root Sheath Cells and Hair Follicles

“…We also found that the IFN-γ-induced proinflammatory cytokines and chemokines of AA ( Figure 3 ) were suppressed by MSCT in hORSCs [ 37 , 38 ]. Due to the inflammatory response, these molecules disrupt the immune privilege of HFs, induce dystrophic change and catagen, and prevent anagen re-entry.…”

“…We previously studied the efficacy of MSCT in hDPCs, one of the key cells that make up the hair bulge [ 37 ]. There are similarities and differences between the results of that study and the results of the current research.…”

Increase in IL-15 levels in patients with alopecia areata

“…The drug increased the expression of some growth factors, and also inhibited the phosphorylation of JAK1, JAK2, JAK3, STAT1 and STAT3. Study results suggest that ruxolitinib therapy may prevent interferon gamma-induced hair loss [39].…”

Recreation of a hair follicle regenerative microenvironment: Successes and pitfalls

“…The impact of JAK/STAT inhibitors on the inductive capacity of hDP cells was showed when tofacitinibtreated hDP spheroids displayed improved HF induction rate than those treated with ruxolitinib, which performed similarly to non-treated spheroids 69 . The treatment with tofacitinib upregulated TGF-β2, BMP6, and LEF1 expression 69 whilst ruxolitinib improved β-catenin gene expression but decrease TGF-β2 expression 70 . This suggests a TGF-β2 mediated hair growth after inhibition of the JAK/STAT signaling pathway.…”