Topical VX-509 attenuates psoriatic inflammation through the STAT3/FABP5 pathway in keratinocytes

Abstract

BackgroundPsoriasis is a chronic inflammatory disease, with lesions mainly manifesting as scaly erythematous plaques. The mild or moderate of psoriasis is the main type of patients in hospital, and topical application remains the preferred treatment option for psoriasis therapy, therefore, the development of novel topical agents has an essential role in psoriasis therapy. ObjectiveTo identify potential drugs for psoriasis topical treatment. MethodsWe performed drug screening by Imiquimod (IMQ)-induced psoriatic like inflammation in mouse model, followed mouse epidermis by RNA-seq to find the key molecules affecting the drug. The qRT-PCR, WB were performed to test mRNA and protein expression, and Chip assay had been conducted to examine Stat3 bound to promoter of FABP5. ResultsIn this study, we identified VX-509, which topical application significantly attenuated IMQ-induced psoriatic like inflammation in mouse model. And then, we verified Epidermal Fatty acid binding protein (E-FABP/FABP5) was significantly decreased in VX-509 treated mouse epidermis by RNA-seq. FABP5 is a key molecule in lipid metabolism, administration of FABP5 inhibitor or knock down of FABP5 expression remarkably abrogated psoriatic inflammation as well as lipid metabolism. Mechanistically, our finding showed that VX-509 blocked IL-22 induced signaling pathway, particular in activation of Stat3. Furthermore, we identified Stat3 is a transcriptional factor associated with FABP5 promoters and VX-509 treatment remarkably attenuated IL-22-induced FABP5 expression through Stat3 in KCs. ConclusionsThis study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy.