title: Uric acid induces trophoblast IL-1β production via the inflammasome: implications for the pathogenesis of preeclampsia.
abstract: OBJECTIVE
  Preeclampsia is associated with hyperuricemia, which correlates with the disease severity. Levels of circulating uric acid increase before the clinical manifestations, suggesting that they may be causally related. Uric acid, or monosodium urate (MSU), activates the Nod-like receptor, Nalp3, leading to inflammasome activation and IL-1β processing. Because preeclampsia is associated with placental immune⁄ inflammatory dysregulation, we sought to determine in the trophoblast, the presence of the Nalp3 inflammasome, and the effect of MSU on its activation.
  
  
  METHODS
  Isolated first- and third-trimester trophoblasts were assessed for expression of the inflammasome components, Nalp1, Nalp3, and ASC. First-trimester trophoblast cells were incubated with or without MSU, and after which, IL-1β secretion and processing and caspase-1 activation were determined.
  
  
  RESULTS
  Trophoblast cells expressed Nalp1, Nalp3, and ASC under basal conditions. Following incubation with MSU, first-trimester trophoblast IL-1β secretion was upregulated. This correlated with increased expression levels of active IL-1β and active caspase-1. ASC knockdown reduced MSU-induced IL-1β secretion.
  
  
  CONCLUSIONS
  These findings demonstrate that uric acid activates the inflammasome in the trophoblast, leading to IL-1β production. This may provide a novel mechanism for the induction of inflammation at the maternal–fetal interface leading to placental dysfunction and adverse pregnancy outcome, including preeclampsia.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University, New Haven, CT 06510, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Mulla
authors.forename: Kledia
authors.initials: K
authors.lastname: Myrtolli
authors.forename: Julie
authors.initials: J
authors.lastname: Potter
authors.forename: Crina
authors.initials: C
authors.lastname: Boeras
authors.forename: Paula B
authors.initials: PB
authors.lastname: Kavathas
authors.forename: Anna K
authors.initials: AK
authors.lastname: Sfakianaki
authors.forename: Serkelem
authors.initials: S
authors.lastname: Tadesse
authors.forename: Errol R
authors.initials: ER
authors.lastname: Norwitz
authors.forename: Seth
authors.initials: S
authors.lastname: Guller
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D033461:Hyperuricemia; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D033261:Maternal-Fetal Relations; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D011225:Pre-Eclampsia / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D011247:Pregnancy; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014527:Uric Acid / Q000097:blood / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D014527:Uric Acid; D020170:Caspase 1