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.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / immunology
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Apoptosis Regulatory Proteins / genetics*
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Apoptosis Regulatory Proteins / immunology
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Caspases / genetics*
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Caspases / immunology
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Cells, Cultured
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DNA / genetics
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DNA / immunology
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Gene Expression Regulation
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Humans
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Inflammasomes / drug effects
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Inflammasomes / immunology
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Interferon-gamma / pharmacology
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Interleukin-17 / antagonists & inhibitors
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Interleukin-17 / genetics*
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Interleukin-17 / immunology
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Interleukin-17 / pharmacology
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Interleukin-1beta / genetics*
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Keratinocytes / immunology
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NLR Proteins
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Psoriasis / genetics*
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Psoriasis / immunology
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Psoriasis / pathology
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S100 Calcium Binding Protein A7
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S100 Proteins / genetics
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S100 Proteins / immunology
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Signal Transduction
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Skin / immunology*
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Skin / pathology
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Th17 Cells / pathology
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Transfection
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Vitamin D / pharmacology
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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IL17A protein, human
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IL1B protein, human
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Inflammasomes
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Interleukin-17
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Interleukin-1beta
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NLR Proteins
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NLRP1 protein, human
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S100 Calcium Binding Protein A7
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S100 Proteins
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S100A7 protein, human
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Vitamin D
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Interferon-gamma
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DNA
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CASP5 protein, human
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Caspases
Grants and funding
This work was supported by grants from the Else Kröner-Fresenius-Foundation (R.W., 2012_A294), the German Research Foundation (S.R., GRK1202; A.S., SCHM 2670/1-1), and the Otto Braun-Falco Scholarship (A.B.B). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.