Sterile intra-amniotic inflammation is commonly observed in patients with spontaneous preterm labor and intact membranes. Indeed, sterile intra-amniotic inflammation is more common than microbial-associated intra-amniotic inflammation in such patients. However, the mechanisms leading to sterile intra-amniotic inflammation are poorly understood and no treatment exists for this condition.
PRB researchers studied whether the alarmin S100B could induce sterile intra-amniotic inflammation by activating the NLRP3 inflammasome, and whether inhibition of this pathway could prevent preterm labor/birth and adverse neonatal outcomes. Ultrasound-guided intra-amniotic administration of S100B into pregnant mice 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, the team reported that S100B caused a proinflammatory response in the amniotic cavity and induced activation of the NLRP3 inflammasome in the fetal membranes, indicated by 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 indicates 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. Such findings provide evidence that sterile intra-amniotic inflammation could be treated by targeting the NLRP3 inflammasome.