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PLoS One. 2017 Apr 19;12(4):e0175153. doi: 10.1371/journal.pone.0175153. eCollection 2017.

Th17 micro-milieu regulates NLRP1-dependent caspase-5 activity in skin autoinflammation.

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Department of Dermatology and Allergology, Ludwig-Maximilian University Munich, Frauenlobstr. 9-11, Munich, Germany.
Department of Dental Medicine, Karolinska Institute, Alfred Nobels Allé 8, Huddinge, Sweden.
Department of Dermatology, Venereology and Allergy, Wroclaw Medical University, Chalubinskiego 1, Wroclaw, Poland.
Division of Clinical Pharmacology, Medizinische Klinik IV, Ludwig-Maximilian University Munich, Ziemssenstr. 1, Munich, Germany.
Department of Dermatology, University Hospital Düsseldorf, Moorenstrasse 5, Düsseldorf, Germany.
Department of Dermatology, University Hospital of Lausanne, CHUV University Hospital, Rue du Bugnon 46, Lausanne, Switzerland.
Department of Dermatology and Allergology, Philipps University Marburg, Marburg, Germany.


IL-1β is a potent player in cutaneous inflammation and central for the development of a Th17 micro-milieu in autoinflammatory diseases including psoriasis. Its production is controlled at the transcriptional level and by subsequent posttranslational processing via inflammatory caspases. In this study, we detected inflammatory caspase-5 active in epidermal keratinocytes and in psoriatic skin lesions. Further, interferon-γ and interleukin-17A synergistically induced caspase-5 expression in cultured keratinocytes, which was dependent on the antimicrobial peptide psoriasin (S100A7). However, diseases-relevant triggers for caspase-5 activity and IL-1β production remain unknown. Recently, extranuclear DNA has been identified as danger-signals abundant in the psoriatic epidermis. Here, we could demonstrate that cytosolic double-stranded (ds) DNA transfected into keratinocytes triggered the activation of caspase-5 and the release of IL-1β. Further, interleukin-17A promoted caspase-5 function via facilitation of the NLRP1-inflammasome. Anti-inflammatory vitamin D interfered with the IL-1β release and suppressed caspase-5 in keratinocytes and in psoriatic skin lesions. Our data link the disease-intrinsic danger signals psoriasin (S100A7) and dsDNA for NLPR1-dependent caspase-5 activity in psoriasis providing potential therapeutic targets in Th17-mediated skin autoinflammation.

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