title: Uric Acid Crystals Induce Placental Inflammation and Alter Trophoblast Function via an IL-1-Dependent Pathway: Implications for Fetal Growth Restriction.
abstract: Excessive placental inflammation is associated with several pathological conditions, including stillbirth and fetal growth restriction. Although infection is a known cause of inflammation, a significant proportion of pregnancies have evidence of inflammation without any detectable infection. Inflammation can also be triggered by endogenous mediators, called damage associated molecular patterns or alarmins. One of these damage-associated molecular patterns, uric acid, is increased in the maternal circulation in pathological pregnancies and is a known agonist of the Nlrp3 inflammasome and inducer of inflammation. However, its effects within the placenta and on pregnancy outcomes remain largely unknown. We found that uric acid (monosodium urate [MSU]) crystals induce a proinflammatory profile in isolated human term cytotrophoblast cells, with a predominant secretion of IL-1β and IL-6, a result confirmed in human term placental explants. The proinflammatory effects of MSU crystals were shown to be IL-1-dependent using a caspase-1 inhibitor (inhibits IL-1 maturation) and IL-1Ra (inhibits IL-1 signaling). The proinflammatory effect of MSU crystals was accompanied by trophoblast apoptosis and decreased syncytialization. Correspondingly, administration of MSU crystals to rats during late gestation induced placental inflammation and was associated with fetal growth restriction. These results make a strong case for an active proinflammatory role of MSU crystals at the maternal-fetal interface in pathological pregnancies, and highlight a key mediating role of IL-1. Furthermore, our study describes a novel in vivo animal model of noninfectious inflammation during pregnancy, which is triggered by MSU crystals and leads to reduced fetal growth.
authors.affiliation: Ste-Justine Hospital Research Centre, Feto-Maternal and Neonatal Pathologies Research Axis, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Obstetrics and Gynecology, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Microbiology, Virology and Immunology, University of Montreal, Montreal, Quebec H3T 1C5, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Brien
authors.affiliation: Ste-Justine Hospital Research Centre, Feto-Maternal and Neonatal Pathologies Research Axis, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Obstetrics and Gynecology, University of Montreal, Montreal, Quebec H3T 1C5, Canada.
authors.forename: Cyntia
authors.identifier: 0000-0002-0247-1231
authors.initials: C
authors.lastname: Duval
authors.affiliation: Ste-Justine Hospital Research Centre, Feto-Maternal and Neonatal Pathologies Research Axis, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Obstetrics and Gynecology, University of Montreal, Montreal, Quebec H3T 1C5, Canada.
authors.forename: Julia
authors.identifier: 0000-0002-7837-4614
authors.initials: J
authors.lastname: Palacios
authors.affiliation: Ste-Justine Hospital Research Centre, Feto-Maternal and Neonatal Pathologies Research Axis, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Obstetrics and Gynecology, University of Montreal, Montreal, Quebec H3T 1C5, Canada.
authors.forename: Ines
authors.initials: I
authors.lastname: Boufaied
authors.affiliation: Institut de la Recherche Scientifique, Centre Institut Armand-Frappier, Laval, Quebec H7V 1B7, Canada.
authors.forename: Andrée-Anne
authors.initials: AA
authors.lastname: Hudon-Thibeault
authors.affiliation: Ste-Justine Hospital Research Centre, Feto-Maternal and Neonatal Pathologies Research Axis, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, University de Montreal, Montreal H3T 1C5, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Nadeau-Vallée
authors.affiliation: Institut de la Recherche Scientifique, Centre Institut Armand-Frappier, Laval, Quebec H7V 1B7, Canada.
authors.forename: Cathy
authors.initials: C
authors.lastname: Vaillancourt
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, M13 9WL, United Kingdom.|St. Mary's Hospital, Central Manchester University Hospital National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, United Kingdom; and.
authors.forename: Colin P
authors.identifier: 0000-0002-2713-0492
authors.initials: CP
authors.lastname: Sibley
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, CT 06510.
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, M13 9WL, United Kingdom.|St. Mary's Hospital, Central Manchester University Hospital National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, United Kingdom; and.
authors.forename: Rebecca L
authors.identifier: 0000-0002-8871-0589
authors.initials: RL
authors.lastname: Jones
authors.affiliation: Ste-Justine Hospital Research Centre, Feto-Maternal and Neonatal Pathologies Research Axis, University of Montreal, Montreal, Quebec H3T 1C5, Canada; sylvie.girard@recherche-ste-justine.qc.ca.|Department of Obstetrics and Gynecology, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Microbiology, Virology and Immunology, University of Montreal, Montreal, Quebec H3T 1C5, Canada.|Department of Pharmacology, University de Montreal, Montreal H3T 1C5, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Girard
mesh_terms: D000818:Animals; D002821:Chorioamnionitis / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005317:Fetal Growth Retardation / Q000276:immunology*; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014327:Trophoblasts / Q000473:pathology*; D014527:Uric Acid / Q000276:immunology*
chemical_list: D007375:Interleukin-1; D014527:Uric Acid