1. Academic Validation
  2. Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis

Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis

  • J Allergy Clin Immunol. 2019 Oct;144(4):1036-1049. doi: 10.1016/j.jaci.2019.06.019.
Kenji Sakurai 1 Teruki Dainichi 2 Sandra Garcet 3 Soken Tsuchiya 4 Yosuke Yamamoto 1 Akihiko Kitoh 1 Tetsuya Honda 1 Takashi Nomura 1 Gyohei Egawa 1 Atsushi Otsuka 1 Saeko Nakajima 1 Reiko Matsumoto 1 Yuri Nakano 1 Masayuki Otsuka 1 Yoichiro Iwakura 5 Yenkel Grinberg-Bleyer 6 Sankar Ghosh 6 Yukihiko Sugimoto 4 Emma Guttman-Yassky 7 James G Krueger 3 Kenji Kabashima 8
Affiliations

Affiliations

  • 1 Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 2 Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: dainichi@kuhp.kyoto-u.ac.jp.
  • 3 Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
  • 4 Department of Pharmaceutical Biochemistry, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan.
  • 5 Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
  • 6 Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY.
  • 7 Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 8 Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Singapore Immunology Network (SIgN) and Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore. Electronic address: kaba@kuhp.kyoto-u.ac.jp.
Abstract

Background: Psoriasis is a chronic inflammatory skin disease characterized by IL-17-mediated immune responses. p38 is known to be highly activated in the psoriatic epidermis; however, whether p38 is involved in the development of psoriasis is unclear.

Objective: We sought to demonstrate that activation of p38 mitogen-activated protein kinase is sufficient to induce psoriatic inflammation in mice and that cutaneous p38 activities are the topical therapeutic targets for psoriasis.

Methods: A p38 activator, anisomycin, was applied daily to murine skin. Transcriptomic analyses were performed to evaluate the similarities of the skin responses to those in human psoriasis and the existing animal model. BIRB796, a small-molecule inhibitor targeting p38 activities, was applied to the murine psoriatic models topically or to human psoriatic skin specimens ex vivo.

Results: Topical treatment with anisomycin induced key signatures in psoriasis, such as epidermal thickening, neutrophil infiltration, and gene expression of Il1a, Il1b, Il6, Il24, Cxcl1, Il23a, and Il17a, in treated murine skin. These responses were fully abrogated by topical treatment with BIRB796, and were reduced in IL-17A-deficient mice. Transcriptomic analyses demonstrated the similarities of anisomycin-induced dermatitis to human psoriasis and imiquimod-induced murine psoriatic dermatitis. Furthermore, BIRB796 targeting of p38 activities reduced expression of psoriasis-related genes in both human keratinocytes stimulated with recombinant IL-17A in vitro and psoriatic skin specimens ex vivo.

Conclusion: Therefore our findings suggest that cutaneous p38 activation can be a key event in patients with psoriasis and a potential topical therapeutic target of a small molecule.

Keywords

IL-17; Psoriasis; anisomycin; p38 mitogen-activated protein kinase.

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