JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis.

ABSTRACT Background Janus kinase (JAK) inhibitors are a new class of therapeutic compounds for dermatological diseases. In atopic dermatitis (AD), data of clinical phase III trials show rapid improvement of pruritus and significant reduction of inflammation within the first weeks with a favourable safety profile. However, their mode of action in AD is not fully understood. Objective In our study, we investigate the effect of different JAK inhibitors on cell differentiation, phenotype, and function of inflammatory dendritic epidermal cells (IDEC). Methods We analysed the JAK expression in IDEC from ex vivo skin and in vitro generated IDEC using flow cytometry and PCR. Further, we studied in vitro the effect of different JAK inhibitors on IDEC cell differentiation, phenotype, and maturation. Results IDEC express JAK1 and JAK2 ex vivo and in vitro. We found that JAK1 and JAK2 were upregulated during the differentiation from monocytes to IDEC. Conversely, JAK2 inhibition by Ruxolitinib (JAK1/2 inhibitor) or BMS-911543 (JAK2 inhibitor) abrogated the differentiation from monocytes into IDEC. Differentiated IDEC can re-differentiate into a more monocyte-like phenotype in the presence of Ruxolitinib or BMS-911543. Furthermore, we showed that concomitant inhibition of JAK1/2 rather than blocking JAK1 or JAK2 alone, impaired maturation and the release of proinflammatory cytokines upon lipopolysaccharide stimulation. Conclusion Our results suggest that inhibition of JAK1/2 impairs IDEC differentiation and function. We provide new insight into the mode of action of JAK inhibitors in AD and highlight the role of JAK1/2 inhibitors for the treatment of AD patients.