title: Barrier abnormality due to ceramide deficiency leads to psoriasiform inflammation in a mouse model.
abstract: 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 β-defensins. In the skin lesions and draining lymph nodes, there were increased numbers of γδ T cells that produced IL-17 (γδ-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 γδ-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 γδ-17 cells.
authors: Department of Dermatology, Kochi Medical School Kochi University, Nankoku, Japan.
authors: Kimiko
authors: K
authors: Nakajima
authors: Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Mika
authors: M
authors: Terao
authors: Department of Dermatology, Kochi Medical School Kochi University, Nankoku, Japan.
authors: Mikiro
authors: M
authors: Takaishi
authors: Science Research Center, Kochi University, Nankoku, Japan.
authors: Sayo
authors: S
authors: Kataoka
authors: Department of Health Promotion Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan; Department of Cell Biology and Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Naoko
authors: N
authors: Goto-Inoue
authors: Department of Cell Biology and Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Mitsutoshi
authors: M
authors: Setou
authors: Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Kyoji
authors: K
authors: Horie
authors: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Fumiko
authors: F
authors: Sakamoto
authors: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Masaaki
authors: M
authors: Ito
authors: Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Hiroaki
authors: H
authors: Azukizawa
authors: Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Shun
authors: S
authors: Kitaba
authors: Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Hiroyuki
authors: H
authors: Murota
authors: Department of Regenerative Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Satoshi
authors: S
authors: Itami
authors: Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Ichiro
authors: I
authors: Katayama
authors: Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Junji
authors: J
authors: Takeda
authors: Department of Dermatology, Kochi Medical School Kochi University, Nankoku, Japan. Electronic address: sano.derma@kochi-u.ac.jp.
authors: Shigetoshi
authors: S
authors: Sano
mesh_terms: D000818:Animals; D002518:Ceramides / Q000172:deficiency*; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051102:Serine C-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014867:Water / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D002518:Ceramides; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D051102:Serine C-Palmitoyltransferase; D014867:Water; D000097043:Interleukin-22; C495090:Sptlc2 protein, mouse