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

• Published in: Cell death & disease Vol. 11; no. 8; p. 617
• Main Authors: Katata, Yu, Inoue, Shin-ichi, Asao, Atsuko, Kobayashi, Shuhei, Terui, Hitoshi, Inoue-Shibui, Aya, Abe, Taiki, Niihori, Tetsuya, Aiba, Setsuya, Ishii, Naoto, Kure, Shigeo, Aoki, Yoko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-08-2020; Springer Nature B.V
• Subjects: 13/106; 13/21; 13/95; 631/250/127/1213; 64/60; 692/699/249/2510/1415; 82/51; Allergens; Animal models; Animals; Antibodies; Atopic dermatitis; Benzamides - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell proliferation; Cell Proliferation - drug effects; Costello Syndrome - complications; Costello Syndrome - genetics; Costello Syndrome - pathology; Cytokines; Cytokines - metabolism; Dermatitis; Dermatitis, Atopic - complications; Dermatitis, Atopic - genetics; Dermatitis, Atopic - parasitology; Dermatitis, Atopic - pathology; Dermis; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacology; Disease Models, Animal; Disease Susceptibility; Ear - pathology; Eczema; Epidermis; Epidermis - drug effects; Epidermis - parasitology; Epidermis - pathology; Epithelial cells; Hereditary diseases; Immunoglobulin E; Immunology; Inflammation Mediators - metabolism; Interleukin-33 - metabolism; Keratinocytes; Keratosis; Leukocytes (basophilic); Life Sciences; Lymphocytes T; Lymphoid cells; Male; Mast cells; MEK inhibitors; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Models, Biological; Mutation; Mutation - genetics; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins p21(ras) - genetics; Pruritus; Pruritus - complications; Pruritus - pathology; Pyroglyphidae - drug effects; Pyroglyphidae - physiology; Skin diseases; Skin lesions
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02845-8

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 (
Hras
G12S/+
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
Hras
G12S/+
mice compared with
Hras
+/+
mice. Cultured
Hras
G12S/+
keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in
Hras
G12S/+
mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of
Hras
G12S/+
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
Hras
G12S/+
mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.