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Fetal and maternal NLRP3 signaling is required for preterm labor and birth
Kenichiro Motomura, … , Adi L. Tarca, Nardhy Gomez-Lopez
Kenichiro Motomura, … , Adi L. Tarca, Nardhy Gomez-Lopez
Published August 22, 2022
Citation Information: JCI Insight. 2022;7(16):e158238. https://doi.org/10.1172/jci.insight.158238.
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Research Article Immunology Reproductive biology

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

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Abstract

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.

Authors

Kenichiro Motomura, Roberto Romero, Jose Galaz, Li Tao, Valeria Garcia-Flores, Yi Xu, Bogdan Done, Marcia Arenas-Hernandez, Derek Miller, Pedro Gutierrez-Contreras, Marcelo Farias-Jofre, Siddhesh Aras, Lawrence I. Grossman, Adi L. Tarca, Nardhy Gomez-Lopez

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Figure 11

Fetal and maternal contribution of NLRP3 to the onset of preterm birth and subsequent neonatal mortality.

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Fetal and maternal contribution of NLRP3 to the onset of preterm birth a...
(A) Mating strategies and resulting fetal genotypes. Nlrp3+/+ dams carrying Nlrp3+/+ fetuses, Nlrp3+/+ dams carrying Nlrp3+/– fetuses, Nlrp3–/– dams carrying Nlrp3+/– fetuses, and Nlrp3–/– dams carrying Nlrp3–/– fetuses were injected with LPS (100 ng/25 μL) on 16.5 days post coitum (dpc) (n = 11–14 per group). (B) Preterm birth rates. (C) Gestational lengths. (D) Mortality rates of neonates. (E) Experimental design for embryo transfer. Nlrp3+/+ dams carrying Nlrp3–/– fetuses and Nlrp3–/– dams carrying Nlrp3+/+ fetuses were injected with LPS (100 ng/25 μL) on 16.5 dpc (n = 11–14 per group). (F) Preterm birth rates. (G) Gestational lengths. (H) Mortality rates of neonates. The P values for the rates of preterm birth and neonatal mortality were determined by Fisher’s exact test. The P values for the gestational lengths were determined by Gehan-Breslow-Wilcoxon test. *P < 0.05; ***P < 0.001.

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ISSN 2379-3708

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