title: Serum amyloid A induces interleukin-1β secretion from keratinocytes via the NACHT, LRR and PYD domains-containing protein 3 inflammasome.
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.
authors.affiliation: Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China.
authors.forename: N
authors.initials: N
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Yi
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D002352:Carrier Proteins; C508717:IL17A protein, human; C508585:IL1B protein, human; D058847:Inflammasomes; D020381:Interleukin-17; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D000685:Serum Amyloid A Protein; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: IL-1β; inflammasome; keratinocytes; psoriasis; serum amyloid A