Fetal and maternal NLRP3 signaling is required for preterm labor and birth

JCI Insight. 2022 Aug 22;7(16):e158238. doi: 10.1172/jci.insight.158238.


Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every 4 preterm neonates is born to a mother with intra-amniotic inflammation driven by invading bacteria. However, the molecular mechanisms underlying this hostile immune response remain unclear. Here, we used a translationally relevant model of preterm birth in Nlrp3-deficient and -sufficient pregnant mice to identify what we believe is a previously unknown dual role for the NLRP3 pathway in the fetal and maternal signaling required for the premature onset of the labor cascade leading to fetal injury and neonatal death. Specifically, the NLRP3 sensor molecule and/or inflammasome is essential for triggering intra-amniotic and decidual inflammation, fetal membrane activation, uterine contractility, and cervical dilation. NLRP3 also regulates the functional status of neutrophils and macrophages in the uterus and decidua, without altering their influx, as well as maternal systemic inflammation. Finally, both embryo transfer experimentation and heterozygous mating systems provided mechanistic evidence showing that NLRP3 signaling in both the fetus and the mother is required for the premature activation of the labor cascade. These data provide insights into the mechanisms of fetal-maternal dialog in the syndrome of preterm labor and indicate that targeting the NLRP3 pathway could prevent adverse perinatal outcomes.

Keywords: Cellular immune response; Immunology; Molecular biology; Obstetrics/gynecology; Reproductive Biology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Female
  • Fetus / metabolism
  • Humans
  • Infant, Newborn
  • Inflammation
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Obstetric Labor, Premature* / genetics
  • Obstetric Labor, Premature* / metabolism
  • Pregnancy
  • Premature Birth* / etiology
  • Premature Birth* / genetics
  • Premature Birth* / metabolism


  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse