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

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 stud...

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Bibliographic Details
Published in:PloS one 2017, Vol.12 (4), p.e0175153-e0175153
Main Authors: Zwicker, Stephanie, Hattinger, Eva, Bureik, Daniela, Batycka-Baran, Aleksandra, Schmidt, Andreas, Gerber, Peter-Arne, Rothenfusser, Simon, Gilliet, Michel, Ruzicka, Thomas, Wolf, Ronald
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - immunology
Apoptosis
Apoptosis Regulatory Proteins - genetics
Apoptosis Regulatory Proteins - immunology
Autoimmune diseases
Biology and Life Sciences
Biopsy
Caspase
Caspase-5
Caspases - genetics
Caspases - immunology
Cell culture
Cells, Cultured
Cytokines
Deoxyribonucleic acid
Dermatology
DNA
DNA - genetics
DNA - immunology
Epidermis
Gene expression
Gene Expression Regulation
Hazards
Helper cells
Hospitals
Humans
Inflammasomes
Inflammasomes - drug effects
Inflammasomes - immunology
Inflammation
Inflammatory diseases
Interferon
Interferon-gamma - pharmacology
Interleukin 1
Interleukin-17 - antagonists & inhibitors
Interleukin-17 - genetics
Interleukin-17 - immunology
Interleukin-17 - pharmacology
Interleukin-1beta - genetics
Interleukin-1beta - immunology
Interleukin-1beta - secretion
Keratinocytes
Keratinocytes - cytology
Keratinocytes - drug effects
Keratinocytes - immunology
Lesions
Lymphocytes
Lymphocytes T
Medicin och hälsovetenskap
Medicine and Health Sciences
Physical sciences
Psoriasis
Psoriasis - genetics
Psoriasis - immunology
Psoriasis - pathology
S100 Calcium Binding Protein A7
S100 Proteins - genetics
S100 Proteins - immunology
Signal Transduction
Skin - immunology
Skin - pathology
Skin diseases
Th17 Cells - drug effects
Th17 Cells - immunology
Th17 Cells - pathology
Transcription
Transfection
Vitamin D
Vitamin D - pharmacology
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0175153