Costello syndrome model mice with a Hras G12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis

Yu Katata, Shin ichi Inoue, Atsuko Asao, Shuhei Kobayashi, Hitoshi Terui, Aya Inoue-Shibui, Taiki Abe, Tetsuya Niihori, Setsuya Aiba, Naoto Ishii, Shigeo Kure, Yoko Aoki

研究成果: Article

抄録

Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (HrasG12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.

本文言語English
論文番号617
ジャーナルCell Death and Disease
11
8
DOI
出版ステータスPublished - 2020 8 1

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

フィンガープリント 「Costello syndrome model mice with a Hras <sup> G12S/+</sup> mutation are susceptible to develop house dust mite-induced atopic dermatitis」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル