Ceramide deficiency in the epidermis leads to development of psoriasis-like lesions associated with IL-23-dependent proliferation of γδ-17 cells (62.1)

Abstract

Abstract It has been recognized that ceramide levels are decreased in the epidermis of patients with atopic dermatitis and psoriasis. However, the underlying mechanism by which ceramide deficiency leads to skin inflammation still remains unclear. Here, we generated Sptlc2 targeted mice under control of the keratin 5 promoter (referred to as K5-SPT-KO mice), by which their keratinocytes were devoid of serine palmitoyltransferase (SPT), the rate-limiting enzyme for de novo sphingolipid synthesis. K5-SPT-KO mice have decreased levels of ceramide in the epidermis and these mice demonstrate barrier dysfunction. From 2 weeks of age, they develop skin inflammation, showing psoriasis-like histopathologic changes and inflammatory cell infiltrates in the dermis. While expression of IFN-γ was not observed in the inflamed skin and draining lymph nodes, increased levels of IL-17 and IL-22 were detected. Strikingly, K5-SPT-KO mice showed increased numbers of γδ-T cells that produce IL-17 (γδ-17) in the skin lesion and lymph nodes and most of them also produce IL-22, similar to Th17 cells. However, much fewer γδ-17 cells are detected in the skin and lymph nodes of wild-type mice. In vivo administration of anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the number of γδ-17 cells in K5-SPT-KO mice. Therefore, we conclude that ceramide deficiency in the epidermis results in the development of psoriasis-like lesions, likely mediated by IL-23-dependent γδ-17 cells in mice.