Impaired NLRP3 inflammasome activity during fetal development regulates IL-1 beta production in human monocytes

Interleukin-1 (IL-1) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll-like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16(pos) monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro-IL-1 precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1 are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL-1. The lack of secreted IL-1 in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase-1 activity before 29 weeks of gestation, whereas expression of the apoptosis-associated speck-like protein containing a CARD and function of the P2x7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP-induced caspase-1 activity in cord blood monocytes. Lastly, secretion of IL-1 in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL-1 responses early in gestation, in part due to a downregulation of TLR-mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus.