Costello syndrome model mice with a HRAS G12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis.
Costello syndrome model mice with a HRAS G12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis.
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具有 HRAS G12S/ 突变的科斯特洛综合征模型小鼠容易患上屋尘螨诱发的特应性皮炎。
DOI：
10.1038/s41419-020-02845-8
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发表时间：
2020
影响因子：
9
通讯作者：
Aoki Y
中科院分区：
文献类型：
--
作者：
Katata Y;Inoue S-I;Asao A;Kobayashi S;Terui H;Inoue-Shibui A;Abe T;Niihori T;Aiba S;Ishii N;Kure S;Aoki Y
Costello综合征是一种由生殖系HRAS突变引起的常染色体显性遗传疾病。Costello综合征患者表现为颅面畸形、心脏缺陷和癌症易感性，以及皮肤异常，包括乳头状瘤、毛发角化病和湿疹性皮炎。然而，皮肤病学异常的机制仍不清楚。在这里，我们证明了表达anHrasG 12 S突变的敲入小鼠（HrasG 12 S/+小鼠）在用屋尘螨过敏原（粉尘螨，Dfb）刺激后，易发生特应性皮炎（AD）样皮肤病变，包括湿疹、瘙痒、血清IgE水平升高、棘皮病以及真皮中肥大细胞、嗜碱性粒细胞和2型先天性淋巴细胞的浸润。与Hras +/+小鼠相比，Hras G12 S/+小鼠皮肤组织中的屏障功能降低，磷酸化ERK（p-ERK）阳性表皮细胞增殖增加，Th 2型细胞因子以及上皮细胞衍生的细胞因子（包括IL-33）增加。培养的HrasG 12 S/+角质形成细胞在Dfb刺激后表现出IL-33表达增加。MEK抑制剂PD 0325901可改善HrasG 12 S/+小鼠的AD样症状，表现为p-ERK阳性表皮细胞增殖减少和IL-33表达减少。我们的研究结果表明，Dfb刺激HrasG 12 S/+小鼠表皮强烈诱导IL-33表达和2型先天淋巴细胞，导致AD样皮肤病变。这些结果表明，HrasG 12 S/+小鼠的表皮易于发生由屋尘螨变应原刺激的湿疹性皮炎。
Costello syndrome is an autosomal dominant disorder that is caused by germlineHRASmutations. 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 anHrasG12S 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 ofHrasG12S/+mice compared withHras+/+mice. CulturedHrasG12S/+keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms inHrasG12S/+mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis ofHrasG12S/+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 ofHrasG12S/+mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.