Barrier Abnormality Due to Ceramide Deficiency Leads to Psoriasiform Inflammation in a Mouse Model
Barrier Abnormality Due to Ceramide Deficiency Leads to Psoriasiform Inflammation in a Mouse Model
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DOI：
10.1038/jid.2013.199
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发表时间：
2013-11-01
影响因子：
6.5
通讯作者：
Sano, Shigetoshi
中科院分区：
文献类型：
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作者：
Nakajima, Kimiko;Terao, Mika;Sano, Shigetoshi
已经认识到神经酰胺在银屑病和特应性皮炎患者的表皮中减少。在这里，我们产生了Sptlc 2（丝氨酸棕榈酰转移酶长链碱基亚基2）靶向小鼠（SPT-cKO小鼠），从而敲除角质形成细胞中神经酰胺生物合成的关键酶丝氨酸棕榈酰转移酶（SPT）。SPT-cKO小鼠表现出表皮中神经酰胺水平降低，这损害了持水能力和屏障功能。从2周龄开始，它们出现了具有组织学畸变的皮肤病变，包括角化过度、棘皮症、颗粒层丢失和炎性细胞浸润。表皮朗格汉斯细胞表现出持续的活化和增强的迁移到淋巴结。皮肤病变显示银屑病相关基因的上调，如IL-17 A、IL-17 F、IL-22、S100 A8、S100 A9和β-防御素。在皮肤病变和引流淋巴结中，产生IL-17的γ δ T细胞（γ δ-17细胞）数量增加，其中大多数也产生IL-22，Th 17细胞也是如此。此外，在病变中观察到产生IL-23的CD 11 c（+）细胞。用抗IL-12/23 p40抗体体内治疗SPT-cKO小鼠改善了皮肤病变并减少了γ δ-17细胞的数量。因此，我们得出结论，表皮神经酰胺缺乏导致银屑病样病变的小鼠，可能介导的IL-23依赖性IL-22产生γ δ-17细胞。
It has been recognized that ceramides are decreased in the epidermis of patients with psoriasis and atopic dermatitis. Here, we generated Sptlc2 (serine palmitoyltransferase long-chain base subunit 2)-targeted mice (SPT-cKO mice), thereby knocking out serine palmitoyltransferase (SPT), the critical enzyme for ceramide biosynthesis, in keratinocytes. SPT-cKO mice showed decreased ceramide levels in the epidermis, which impaired water-holding capacity and barrier function. From 2 weeks of age, they developed skin lesions with histological aberrations including hyperkeratosis, acanthosis, loss of the granular layer, and inflammatory cell infiltrates. Epidermal Langerhans cells showed persistent activation and enhanced migration to lymph nodes. Skin lesions showed upregulation of psoriasis-associated genes, such as IL-17A, IL-17F, IL-22, S100A8, S100A9, and beta-defensins. In the skin lesions and draining lymph nodes, there were increased numbers of gamma delta T cells that produced IL-17 (gamma delta-17 cells), most of which also produced IL-22, as do Th17 cells. Furthermore, IL-23-producing CD11c(+) cells were observed in the lesions. In vivo treatment of SPT-cKO mice with an anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the numbers of gamma delta-17 cells. Therefore, we conclude that a ceramide deficiency in the epidermis leads to psoriasis-like lesions in mice, probably mediated by IL-23-dependent IL-22-producing gamma delta-17 cells.