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

Summary Interleukin (IL) ‐1β is now emerging as a critical cytokine in the pathogenesis of T helper type 17 ( T h17)‐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 T oll‐like receptor‐2 ( TLR‐ 2), TLR‐ 4 or nuclear factor kappa B ( NF ‐κ B ) attenuated SAA ‐induced expression of IL ‐1β mRNA . SAA up‐regulated caspase‐1 and NACHT, LRR and PYD domains‐containing protein 3 ( NLRP 3) expression in keratinocytes. Inhibiting caspase‐1 activity and silencing NLRP 3 decreased IL ‐1β secretion, confirming NLRP 3 as the SAA ‐responsive inflammasome on the post‐transcriptional level. The mechanism of SAA ‐triggered NLRP 3 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 ‐17 A . Taken together, our results indicate that keratinocyte‐derived SAA triggers a key inflammatory mediator, IL ‐1β, via NLRP 3 inflammasome activation, providing new potential targets for the treatment of this chronic skin disease.