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

Zwicker, Stephanie; Hettinger, Eva; Bureik, Daniela; Batycka-Baran, Aleksandra; Schmidt, Andreas; Gerber, Peter-Arne; Rothenfusser, Simon; Gilliet, Michel; Ruzicka, Thomas and Wolf, Ronald (2017): Th17 micro-milieu regulates NLRP1-dependent caspase-5 activity in skin autoinflammation.
In: PLOS One 12(4), e0175153

Abstract

IL-1 beta 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-gamma 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-1 beta 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-1 beta. Further, interleukin-17A promoted caspase- 5 function via facilitation of the NLRP1-inflammasome. Anti-inflammatory vitamin D interfered with the IL-1 beta 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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1932-6203
• Language: English