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

PLoS One. 2017 Apr 19;12(4):e0175153. doi: 10.1371/journal.pone.0175153. eCollection 2017.

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

  • 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 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / immunology
  • NLR Proteins
  • Psoriasis / genetics*
  • Psoriasis / immunology
  • Psoriasis / pathology
  • S100 Calcium Binding Protein A7
  • 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

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • IL17A protein, human
  • IL1B protein, human
  • Inflammasomes
  • Interleukin-17
  • Interleukin-1beta
  • NLR Proteins
  • NLRP1 protein, human
  • S100 Calcium Binding Protein A7
  • S100 Proteins
  • S100A7 protein, human
  • Vitamin D
  • Interferon-gamma
  • DNA
  • CASP5 protein, human
  • 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.