Specific roles for dendritic cell subsets during initiation and progression of psoriasis

EMBO Molecular Medicine

Elisabeth Glitzner¹  Ana Korosec¹  Patrick M Brunner²  Barbara Drobits¹  Nicole Amberg¹  Helia B Schonthaler³  Tamara Kopp²  Erwin F Wagner³  Georg Stingl²  Martin Holcmann¹ 

[1] Department of Medicine I, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria;Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria;BBVA Foundation–CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

关键词: AP‐1;    IL‐23;    Langerhans cells;    plasmacytoid dendritic cells;    psoriasis;   

DOI  :  10.15252/emmm.201404114

来源: Wiley

【 摘 要 】

Abstract

Several subtypes of APCs are found in psoriasis patients, but their involvement in disease pathogenesis is poorly understood. Here, we investigated the contribution of Langerhans cells (LCs) and plasmacytoid DCs (pDCs) in psoriasis. In human psoriatic lesions and in a psoriasis mouse model (DKO* mice), LCs are severely reduced, whereas pDCs are increased. Depletion of pDCs in DKO* mice prior to psoriasis induction resulted in a milder phenotype, whereas depletion during active disease had no effect. In contrast, while depletion of Langerin-expressing APCs before disease onset had no effect, depletion from diseased mice aggravated psoriasis symptoms. Disease aggravation was due to the absence of LCs, but not other Langerin-expressing APCs. LCs derived from DKO* mice produced increased IL-10 levels, suggesting an immunosuppressive function. Moreover, IL-23 production was high in psoriatic mice and further increased in the absence of LCs. Conversely, pDC depletion resulted in reduced IL-23 production, and therapeutic inhibition of IL-23R signaling ameliorated disease symptoms. Therefore, LCs have an anti-inflammatory role during active psoriatic disease, while pDCs exert an instigatory function during disease initiation.

Synopsis

Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti-inflammatory IL-10 and pro-inflammatory IL-23 axis.

• Langerhans cells (LCs) are severely reduced and plasmacytoid DCs (pDCs) are increased in human psoriasis as well as in mouse models of psoriasis
• Depletion of pDCs in mice prior to psoriasis induction results in disease amelioration whereas depletion during active disease has no effect
• Depletion of LCs during active psoriasis results in disease aggravation whereas depletion before disease initiation has no effect
• The anti-inflammatory role of LCs is mediated by direct release of the immunosuppressive cytokine IL-10 and by preventing excessive IL-23 accumulation in the skin
• pDC depletion results in reduced IL-23 levels and therapeutic inhibition of IL-23 receptor ameliorates disease symptoms

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.