@article{4cc690cfdabf4a569fa602cfcd0cd6ef,
title = "Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes",
abstract = "Sterile intra-amniotic inflammation is commonly observed in patients with spontaneous preterm labor, a syndrome that commonly precedes preterm birth, the leading cause of perinatal morbidity and mortality worldwide. However, the mechanisms leading to sterile intra-amniotic inflammation are poorly understood and no treatment exists for this clinical condition. Herein, we investigated whether the alarmin S100B could induce sterile intra-amniotic inflammation by activating the NLRP3 inflammasome, and whether the inhibition of this pathway could prevent preterm labor/birth and adverse neonatal outcomes. We found that the ultrasound-guided intra-amniotic administration of S100B induced a 50% rate of preterm labor/birth and a high rate of neonatal mortality (59.7%) without altering the fetal and placental weights. Using a multiplex cytokine array and immunoblotting, we reported that S100B caused a proinflammatory response in the amniotic cavity and induced the activation of the NLRP3 inflammasome in the fetal membranes, indicated by the upregulation of the NLRP3 protein and increased release of active caspase-1 and mature IL-1β. Inhibition of the NLRP3 inflammasome via the specific inhibitor MCC950 prevented preterm labor/birth by 35.7% and reduced neonatal mortality by 26.7%. Yet, inhibition of the NLRP3 inflammasome at term did not drastically obstruct the physiological process of parturition. In conclusion, the data presented herein indicate that the alarmin S100B can induce sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes by activating the NLRP3 inflammasome, which can be prevented by inhibiting such a pathway. These findings provide evidence that sterile intra-amniotic inflammation could be treated by targeting the NLRP3 inflammasome.",
keywords = "S100B, acute chorioamnionitis, alarmins, amniotic fluid, caspase-1, cytokines, damage-associated molecular patterns, danger signals, funisitis, inhibitor, interleukin-1β, mice",
author = "Nardhy Gomez-Lopez and Roberto Romero and Valeria Garcia-Flores and Yaozhu Leng and Derek Miller and Hassan, {Sonia S.} and Hsu, {Chaur Dong} and Bogdan Panaitescu",
note = "Funding Information: 1Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA; 2Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA; 3Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USA;4Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA;5Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA; 6Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA and 7Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA ∗Correspondence: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Perinatology Research Branch, NICHD/NIH/DHHS, 275 E. Hancock, Detroit, MI 48201, USA. Tel: +313-577-8904; E-mail: nardhy.gomez-lopez@wayne.edu †Grant support: This research was supported, in part, by the Perinatology Research Branch (PRB), Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), and, in part, with federal funds from the NICHD/NIH/DHHS under Contract No.HHSN275201300006C. This research was also supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. Publisher Copyright: {\textcopyright} 2018 The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction.",
year = "2019",
month = may,
day = "1",
doi = "10.1093/biolre/ioy264",
language = "English (US)",
volume = "100",
pages = "1306--1318",
journal = "Biology of Reproduction",
issn = "0006-3363",
publisher = "Society for the Study of Reproduction",
number = "5",
}