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 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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|Palavras-Chave||#Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/immunology; Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins/immunology; Caspases/genetics; Caspases/immunology; Cells, Cultured; DNA/genetics; DNA/immunology; Gene Expression Regulation; Humans; Inflammasomes/drug effects; Inflammasomes/immunology; Interferon-gamma/pharmacology; Interleukin-17/antagonists & inhibitors; Interleukin-17/genetics; Interleukin-17/immunology; Interleukin-17/pharmacology; Interleukin-1beta/genetics; Interleukin-1beta/immunology; Interleukin-1beta/secretion; Keratinocytes/cytology; Keratinocytes/drug effects; Keratinocytes/immunology; Psoriasis/genetics; Psoriasis/immunology; Psoriasis/pathology; S100 Proteins/genetics; S100 Proteins/immunology; Signal Transduction; Skin/immunology; Skin/pathology; Th17 Cells/drug effects; Th17 Cells/immunology; Th17 Cells/pathology; Transfection; Vitamin D/pharmacology|