Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte-derived chemokine expression and neutrophil infiltration

Psoriasis is an inflammatory autoimmune skin disorder possessing a complex etiology related to genetic and environmental triggers. Keratinocytes show a potential role for the origin of psoriasis. In this study, we estimated the efficiency of 2 anthranilate derivatives—(E)-4-(N-{2-[1-(hydroxyimino)ethyl]phenyl}sulfamoyl)phenyl pivalate (HFP031) and butyl 2-[2-(2-fluorophenyl)acetamido]benzoate (HFP034)—on psoriasis amelioration in a mouse model. The results showed that topical treatment with both compounds could attenuate epidermal thickness and scaling in an imiquimod (IMQ)-induced psoriasis mouse model via decreased expression of cytokines and chemokines [C-X-C chemokine ligand (CXCL)1 and CXCL2], leading to the reduction of neutrophilic abscess in the skin. The in vivo cutaneous absorption of HFP034 was 7.6-fold greater than that of HFP031. Both compounds caused negligible irritation on healthy mouse skin. In addition, we examined the effect of the anthranilate derivatives on chemokine expression in IMQ-treated HaCaT keratinocytes. Our results elucidated a mechanism for anti-inflammatory activity of HFP034 that involved the elevation of intracellular cAMP concentration, suppression of NF-kB activity, and attenuation of neutrophil chemoattractant expression. These results suggest that HFP034 could increase the cutaneous concentration of cAMP to suppress neutrophil infiltration into the skin. Topically applied HFP034 may demonstrate a potential for future clinical application as a novel therapy for psoriasis treatment.