JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases

Ana Karina Alves de Medeiros, Reinhart Speeckaert, Eline Desmet, Mireille Van Gele, Sofie De Schepper, Jo Lambert, Ana Karina Alves de Medeiros, Reinhart Speeckaert, Eline Desmet, Mireille Van Gele, Sofie De Schepper, Jo Lambert

Abstract

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. JAK1, JAK2, JAK3 and TYK2…
Fig 1. JAK1, JAK2, JAK3 and TYK2 immunohistochemical localization in the epidermis.
Similar expression was seen in all studied diseases: JAK1, 2 and 3 were expressed in the cytoplasm of the keratinocytes and TYK2, besides cytoplasmic expression, had nuclear expression of TYK2 (arrow). Original magnification x 200. Pso = psoriasis, LP = lichen planus, CLE = cutaneous lupus erythemathosus, AD = atopic dermatitis, AA = alopecia areata, PG = pyoderma gangrenosum.
Fig 2. PhosphoJAK1, pJAK2, pJAK3 and pTYK2…
Fig 2. PhosphoJAK1, pJAK2, pJAK3 and pTYK2 immunohistochemical localization in the epidermis.
Cytoplasmic expression of pJAK1, pJAK3 and pTYK2. Intranuclear expression of pJAK2 and pTYK2 (arrows). Similar expression was seen in all studied diseases. Original x 200. Pso = psoriasis, LP = lichen planus, CLE = cutaneous lupus erythemathosus, AD = atopic dermatitis, AA = alopecia areata, PG = pyoderma gangrenosum.
Fig 3. Overview of JAK/STAT protein (by…
Fig 3. Overview of JAK/STAT protein (by immunohistochemistry) expression in the studied inflammatory skin diseases as compared to healthy skin.
Pso = psoriasis, LP = lichen planus, CLE = cutaneous lupus erythemathosus, AD = atopic dermatitis, AA = alopecia areata, PG = pyoderma gangrenosum, epid ext = epidermal extent. NS = not statistically significant.
Fig 4. SPSS statistical analysis of the…
Fig 4. SPSS statistical analysis of the keratinocyte staining compared with control (staining intensity for pJAK1 and pJAK3 and density of the positively stained cells for pJAK2, pTYK2, pSTAT1, pSTAT2 and pSTAT3).
Pso = psoriasis, LP = lichen planus, CLE = cutaneous lupus erythemathosus, AD = atopic dermatitis, AA = alopecia areata, PG = pyoderma gangrenosum, epid ext = epidermal extent. NS = not statistically significant. * p≤0.05 ** p≤0.001.
Fig 5. JAK/STAT mRNA levels in human…
Fig 5. JAK/STAT mRNA levels in human skin biopsies from psoriasis compared to healthy controls illustrates JAK3, STAT1 and STAT3 overexpression.
* p≤0.05.
Fig 6. Immunohistochemical staining of normal keratinocytes…
Fig 6. Immunohistochemical staining of normal keratinocytes (KCs) and psoriasis induced keratinocytes (Pso KCs) with or without tofacitinib treatment.
The pJAKs expression in Pso KCs was similar and summarizes the one observed in the epidermis of the psoriasis skin biopsies. Strong pJAK3 expression and weak positive pJAK1 expression was induced by psoriasis stimulation and inhibited after treatment with tofacitinib. Phospho-JAK2 and pTYK2 expression did not change neither with psoriasis stimulation nor with the treatment. Note the cytoplasm localization of pJAK1 and pJAK3 and the nuclear localization of pTYK2 in the keratinocytes. As pJAK2 was negative in all conditions, the localization of the staining could not be analysed. Original magnification x200.

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