title: A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1β production by human first trimester trophoblast.
abstract: Women with antiphospholipid syndrome (APS) are at risk of recurrent pregnancy loss and obstetrical disorders, such as preeclampsia and intrauterine growth restriction (IUGR). Antiphospholipid antibodies (aPL) directly target the placenta by binding beta2-glycoprotein I (β2GPI) expressed on the trophoblast. We recently demonstrated in human first trimester trophoblast cells that anti-β2GPI antibodies (Abs) induce the secretion of IL-1β in a Toll-like receptor 4 (TLR4)-dependent manner. IL-1β secretion requires processing of pro-IL-1β and this is mediated by the inflammasome, a complex of Nalp3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1. The objective of this study was to determine if aPL induce IL-1β production in trophoblast via the inflammasome. Using a human first trimester trophoblast cell line, we demonstrated that a mouse anti-β2GPI mAb and human polyclonal aPL-IgG induce IL-1β processing and secretion, which was partially blocked upon caspase-1 inhibition. Nalp3 and ASC knockdown also attenuated anti-β2GPI Ab-induced IL-1β secretion. Furthermore, aPL stimulated the production of uric acid in a TLR4-dependent manner; and inhibition of uric acid prevented aPL-induced IL-1β production by the trophoblast. These findings demonstrate that aPL, via TLR4 activation, induce a uric acid response in human trophoblast, which in turn activates the Nalp3/ASC inflammasome leading to IL-1β processing and secretion. This novel mechanism may account for the inflammation at the maternal-fetal interface, which causes placental dysfunction and increases the risk of adverse pregnancy outcome in patients with APS.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Mulla
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
authors.forename: Larry W
authors.initials: LW
authors.lastname: Chamley
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
authors.forename: Crina M
authors.initials: CM
authors.lastname: Boeras
authors.forename: Paula B
authors.initials: PB
authors.lastname: Kavathas
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000494:pharmacology*; D016736:Antiphospholipid Syndrome / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014527:Uric Acid / Q000276:immunology* / Q000378:metabolism; D053482:beta 2-Glycoprotein I / Q000235:genetics / Q000276:immunology
chemical_list: D017152:Antibodies, Antiphospholipid; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D011498:Protein Precursors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053482:beta 2-Glycoprotein I; D014527:Uric Acid; D020170:Caspase 1