title: JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases.
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.
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.|Department of Dermatology, Ghent University, Ghent, Belgium.
authors.forename: Ana Karina
authors.initials: AK
authors.lastname: Alves de Medeiros
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.|Department of Dermatology, Ghent University, Ghent, Belgium.
authors.forename: Reinhart
authors.initials: R
authors.lastname: Speeckaert
authors.affiliation: Department of Dermatology, Ghent University, Ghent, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Desmet
authors.affiliation: Department of Dermatology, Ghent University, Ghent, Belgium.
authors.forename: Mireille
authors.initials: M
authors.lastname: Van Gele
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: De Schepper
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.|Department of Dermatology, Ghent University, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Lambert
mesh_terms: D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000150:complications; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012871:Skin Diseases / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D053616:Janus Kinase 3