A key role for NLRP3 signaling in preterm labor and birth driven by the alarmin S100B

Jose Galaz, Kenichiro Motomura, Roberto Romero, Zhenjie Liu, Valeria Garcia-Flores, Li Tao, Yi Xu, Bogdan Done, Marcia Arenas-Hernandez, Tomi Kanninen, Marcelo Farias-Jofre, Derek Miller, Adi L. Tarca, Nardhy Gomez-Lopez

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Preterm birth remains the leading cause of neonatal morbidity and mortality worldwide. A substantial number of spontaneous preterm births occur in the context of sterile intra-amniotic inflammation, a condition that has been mechanistically proven to be triggered by alarmins. However, sterile intra-amniotic inflammation still lacks treatment. The NLRP3 inflammasome has been implicated in sterile intra-amniotic inflammation; yet, its underlying mechanisms, as well as the maternal and fetal contributions to this signaling pathway, are unclear. Herein, by utilizing a translational and clinically relevant model of alarmin-induced preterm labor and birth in Nlrp3−/− mice, we investigated the role of NLRP3 signaling by using imaging and molecular biology approaches. Nlrp3 deficiency abrogated preterm birth and the resulting neonatal mortality induced by the alarmin S100B by impeding the premature activation of the common pathway of labor as well as by dampening intra-amniotic and fetal inflammation. Moreover, Nlrp3 deficiency altered leukocyte infiltration and functionality in the uterus and decidua. Last, embryo transfer revealed that maternal and fetal Nlrp3 signaling contribute to alarmin-induced preterm birth and neonatal mortality, further strengthening the concept that both individuals participate in the complex process of preterm parturition. These findings provide novel insights into sterile intra-amniotic inflammation, a common etiology of preterm labor and birth, suggesting that the adverse perinatal outcomes resulting from prematurity can be prevented by targeting NLRP3 signaling.

Original languageEnglish
Pages (from-to)46-61
Number of pages16
JournalTranslational Research
Volume259
DOIs
StatePublished - Sep 2023

Keywords

  • fetus
  • inflammasome
  • neonate
  • parturition
  • prematurity
  • preterm birth
  • sterile intra-amniotic inflammation

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