NLRP3 inflammasome characterization in first-trimester, preterm, and term human villous placenta

Abstract

Abstract Precise regulation of inflammatory signaling at the maternal-fetal interface is essential for a healthy pregnancy, yet how the NLRP3 inflammasome is regulated in the placenta during pregnancy and in preterm birth remains poorly understood. We characterized NLRP3 inflammasome-associated signaling in human villous placental tissue from first-trimester (8–11 weeks), preterm (28–<37 weeks), and term (38–40 weeks) pregnancies. Gene expression, protein abundance, caspase-1 processing, and tissue cytokine concentrations were assessed using qPCR, western blot, and ELISA, alongside analysis of upstream inflammatory pathways. Distinct patterns were observed at multiple molecular levels. First-trimester placentas showed the highest cytokine concentrations and NLRP3 protein abundance despite low transcript levels. Preterm placentas formed a separate transcriptional cluster and exhibited accumulation of inflammasome precursors, including pro-caspase-1 and full-length gasdermin D, without corresponding caspase-1 activation. Term placentas displayed increased transcriptional activity but reduced protein abundance and IL-1β levels. These findings demonstrate that the villous placenta exhibits distinct inflammasome profiles in first-trimester, preterm, and term pregnancies, with first-trimester placentas showing high cytokine concentrations, and both preterm and term placentas displaying a state of transcriptional priming without proportional downstream activation — consistent with a ‘primed but restrained’ inflammasome phenotype in later gestation.