Serum amyloid A triggers the mosodium urate -mediated mature interleukin-1β production from human synovial fibroblasts

Abstract

BackgroundMonosodium urate (MSU) has been shown to promote inflammasome activation and interleukin-1β (IL-1β) secretion in monocyte/macrophages, but the cellular pathway and nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in synovial tissues, remain elusive. In this study, we investigated the effects of MSU on synovial fibroblasts to elucidate the process of MSU-mediated synovial inflammation.MethodsHuman synovial fibroblasts were stimulated with MSU in the presence or absence of serum amyloid A (SAA). The cellular supernatants were analyzed by immunoblotting using anti-IL-1β or anti-caspase-1 antibodies. IL-1β or NLRP3 mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method.ResultsNeither SAA nor MSU stimulation resulted in IL-1β or interleukin-1α (IL-1α) secretions and pro-IL-1β processing in synovial fibroblasts. However, in SAA-primed synovial fibroblasts, MSU stimulation resulted in the activation of caspase-1 and production of active IL-1β and IL-1α. The effect of SAA on IL-1β induction was impaired in cells by silencing NLRP3 using siRNA or treating with caspase-1 inhibitor. In addition, SAA induced the secretion of cathepsin B and NLRP3 mRNA expression in synovial fibroblasts.ConclusionsOur data demonstrate that exposure of human synovial fibroblasts to SAA promotes MSU-mediated caspase-1 activation and IL-1β secretion in the absence of microbial stimulation. These findings provide insight into the molecular processes underlying the synovial inflammatory condition of gout.

Serum amyloid A induces interleukin‐6 in dermal fibroblasts via Toll‐like receptor 2, interleukin‐1 receptor‐associated kinase 4 and nuclear factor‐κB

“…29 In RA an increase in SAA has been shown to induce cytoskeletal rearrangement 22 and the production of matrix metalloproteases, 14 and in gout SAA is thought to be involved in activation of the inflammasome. 19 However, Figure 5. Serum amyloid A (SAA) activates Toll-like receptor 2 (TLR2) as effective as the natural ligand but does not activate TLR4.…”

“…SAA has been shown to signal via multiple receptors including TLR2, TLR4 and formyl peptide receptor‐like 1 to induce a variety of functions including pro‐inflammatory cytokine secretion, the metabolism of high‐density lipoproteins and transport of cholesterol . In RA an increase in SAA has been shown to induce cytoskeletal rearrangement and the production of matrix metalloproteases, and in gout SAA is thought to be involved in activation of the inflammasome . However, the functional effect of the increase of SAA levels in SSc patients is, to date, unknown.…”

Inflammasomes contributing to inflammation in arthritis

“…Various stimuli are able to prime monocytes/macrophages for inflammasome activation by pathogenic crystals. Indeed, priming with serum amyloid A (SAA), TLR ligands, or TNF warranted the capacity of MSU to activate the inflammasome and induce release of IL‐1β in human cells . Of interest, also soluble uric acids were able to deliver the priming signal; however, the precipitation of uric acid into MSU crystals was necessary for NLRP3 inflammasome activity .…”

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

“…Recent evidence has indicated that SAA possesses a number of cytokine‐like properties. It has been reported that SAA stimulates the release of mature IL‐1β from neutrophils, mast cells, macrophages and fibroblasts . However, whether or not SAA can induce IL‐1β production in keratinocytes remains to be investigated.…”