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

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Abstract
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‐κB 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.—Lin, Z.‐C., Hsieh, P.‐W., Hwang, T.‐L., Chen, C.‐Y., Sung, C. T., Fang, J.‐Y. Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration. FASEB J. 32, 6783–6795 (2018). www.fasebj.org

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