Topical application of activator protein-1 inhibitor T-5224 suppresses inflammation and improves skin barrier function in a murine atopic dermatitis-like dermatitis

• Published in: Allergology international Vol. 73; no. 2; pp. 323 - 331
• Main Authors: Sasakura, Minori, Urakami, Hitoshi, Tachibana, Kota, Ikeda, Kenta, Hasui, Ken-ichi, Matsuda, Yoshihiro, Sunagawa, Ko, Ennishi, Daisuke, Tomida, Shuta, Morizane, Shin
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.04.2024; Elsevier
• Subjects: Animals; AP-1 inhibitor; Atopic dermatitis; Azetidines; Baricitinib; Benzophenones; Cytokines - metabolism; Dermatitis, Atopic - metabolism; Humans; Inflammation - drug therapy; Interleukin-33; Isoxazoles; Mice; Purines; Pyrazoles; Skin - pathology; Sulfonamides; T-5224; Topical application; Transcription Factor AP-1 - antagonists & inhibitors; FLG; AD; DNFB; qRT-PCR; TYK; MTT; LOR; AP; LDH; T-5224; STAT; AP-1 inhibitor; Atopic dermatitis; JAK; NF; Topical application; Elovl6; Baricitinib; NHEKs
• ISSN: 1323-8930; 1440-1592
• DOI: 10.1016/j.alit.2023.12.006

Selective activator protein (AP)-1 inhibitors are potentially promising therapeutic agents for atopic dermatitis (AD) because AP-1 is an important regulator of skin inflammation. However, few studies have investigated the effect of topical application of AP-1 inhibitors in treating inflammatory skin disorders. Immunohistochemistry was conducted to detect phosphorylated AP-1/c-Jun expression of skin lesions in AD patients. In the in vivo study, 1 % T-5224 ointment was topically applied for 8 days to the ears of 2,4 dinitrofluorobenzene challenged AD-like dermatitis model mice. Baricitinib, a conventional therapeutic agent Janus kinase (JAK) inhibitor, was also topically applied. In the in vitro study, human epidermal keratinocytes were treated with T-5224 and stimulated with AD-related cytokines. AP-1/c-Jun was phosphorylated at skin lesions in AD patients. In vivo, topical T-5224 application inhibited ear swelling (P < 0.001), restored filaggrin (Flg) expression (P < 0.01), and generally suppressed immune-related pathways. T-5224 significantly suppressed Il17a and l17f expression, whereas baricitinib did not. Baricitinib suppressed Il4, Il19, Il33 and Ifnb expression, whereas T-5224 did not. Il1a, Il1b, Il23a, Ifna, S100a8, and S100a9 expression was cooperatively downregulated following the combined use of T-5224 and baricitinib. In vitro, T-5224 restored the expression of FLG and loricrin (LOR) (P < 0.05) and suppressed IL33 expression (P < 0.05) without affecting cell viability and cytotoxicity. Topical T-5224 ameliorates clinical manifestations of AD-like dermatitis in mice. The effect of this inhibitor is amplified via combined use with JAK inhibitors.