Reduced NLRP3, AIM2 and NLRC4 inflammasome activity in cord blood of extremely preterm infants

Background Pro-inflammatory caspase-1 is a key player in innate immunity. Physiological activation of the inflammasome/caspase-1 pathway supports host defense against pathogens, whereas dysregulated activation contributes to the pathogenesis of neonatal diseases such as bronchopulmonary dysplasia. Although preterm infants exhibit reduced IL-1β secretion from monocytes compared with term infants, a comprehensive functional characterization of distinct inflammasome pathways is lacking. Objective To specifically analyze the activity of NLRP3, AIM2 and NLRC4 inflammasomes in cord blood of pre- and full-term infants and in peripheral blood of healthy adults. Methods A validated whole-blood assay was used to specifically activate the different inflammasomes. IL-1β was analyzed as a surrogate marker of inflammasome/caspase-1 activation. RT-qPCR was used to measure expression of inflammasome related genes in leukocytes. Results Activity of the NLRP3 and AIM2 inflammasomes was reduced in cord blood of preterm infants, particularly those born at <28 weeks of gestation, compared with term infants and adults. NLRC4 inflammasome activity was significantly reduced only in preterm infants with gestational age <32 weeks. No significant differences were observed between full-term infants and adult controls. Gene expression analysis revealed an age-dependent upregulation of NLRP3, AIM2, NLRC4, ASC, CASP1 and IL1B, with expression levels increasing from preterm to term gestation and even further towards adulthood. Conclusion Activity of the inflammasome/caspase-1 pathway correlates with gestational age and is significantly reduced in preterm infants compared with full-term infants or adults. This finding contrasts with the high incidence of preterm-specific disorders where dysregulated caspase-1 activation is implicated in disease pathogenesis. Future research should investigate the dynamic evolution of inflammasome activity during the first days of life to elucidate its role in the onset of neonatal diseases.