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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.

Author information

1
Department of Dermatology and Allergology, Ludwig-Maximilian University Munich, Frauenlobstr. 9-11, Munich, Germany.
2
Department of Dental Medicine, Karolinska Institute, Alfred Nobels Allé 8, Huddinge, Sweden.
3
Department of Dermatology, Venereology and Allergy, Wroclaw Medical University, Chalubinskiego 1, Wroclaw, Poland.
4
Division of Clinical Pharmacology, Medizinische Klinik IV, Ludwig-Maximilian University Munich, Ziemssenstr. 1, Munich, Germany.
5
Department of Dermatology, University Hospital Düsseldorf, Moorenstrasse 5, Düsseldorf, Germany.
6
Department of Dermatology, University Hospital of Lausanne, CHUV University Hospital, Rue du Bugnon 46, Lausanne, Switzerland.
7
Department of Dermatology and Allergology, Philipps University Marburg, Marburg, Germany.

Abstract

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.

PMID:
28422993
PMCID:
PMC5396864
DOI:
10.1371/journal.pone.0175153
[Indexed for MEDLINE]
Free PMC Article

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