Serum amyloid A induces interleukin-1β secretion from keratinocytes via the NACHT, LRR and PYD domains-containing protein 3 inflammasome

Clin Exp Immunol. 2015 Feb;179(2):344-53. doi: 10.1111/cei.12458.

Abstract

Interleukin (IL)-1β is now emerging as a critical cytokine in the pathogenesis of T helper type 17 (Th17)-mediated skin diseases, including psoriasis. Psoriatic keratinocytes are a major source of IL-1β; however, the mechanisms triggering IL-1β processing remain unknown. Recently, an acute-phase protein serum amyloid A (SAA) has been identified as a danger signal that triggers inflammasome activation and IL-1β secretion. In this study, we detected increased SAA mRNA and protein expression in psoriatic epidermis. In cultured keratinocytes, SAA up-regulated the expression of pro-IL-1β and secretion of mature IL-1β. On the transcriptional level, blocking Toll-like receptor-2 (TLR-2), TLR-4 or nuclear factor kappa B (NF-κB) attenuated SAA-induced expression of IL-1β mRNA. SAA up-regulated caspase-1 and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) expression in keratinocytes. Inhibiting caspase-1 activity and silencing NLRP3 decreased IL-1β secretion, confirming NLRP3 as the SAA-responsive inflammasome on the post-transcriptional level. The mechanism of SAA-triggered NLRP3 activation and subsequent IL-1β secretion was found to involve the generation of reactive oxygen species. Finally, the expression of SAA by keratinocytes was up-regulated by IL-17A. Taken together, our results indicate that keratinocyte-derived SAA triggers a key inflammatory mediator, IL-1β, via NLRP3 inflammasome activation, providing new potential targets for the treatment of this chronic skin disease.

Keywords: IL-1β; inflammasome; keratinocytes; psoriasis; serum amyloid A.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism
  • Female
  • Humans
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-1beta / immunology*
  • Interleukin-1beta / metabolism
  • Keratinocytes / immunology*
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Male
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Psoriasis / immunology*
  • Psoriasis / metabolism
  • Psoriasis / pathology
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Serum Amyloid A Protein / immunology*
  • Serum Amyloid A Protein / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Th17 Cells / pathology
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • Up-Regulation / immunology

Substances

  • Carrier Proteins
  • IL17A protein, human
  • IL1B protein, human
  • Inflammasomes
  • Interleukin-17
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Reactive Oxygen Species
  • Serum Amyloid A Protein
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4