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

• Published in: European journal of immunology Vol. 45; no. 1; p. 238
• Main Authors: Sharma, Ashish A, Jen, Roger, Kan, Bernard, Sharma, Abhinav, Marchant, Elizabeth, Tang, Anthony, Gadawski, Izabelle, Senger, Christof, Skoll, Amanda, Turvey, Stuart E, Sly, Laura M, Cote, Hélène CF, Lavoie, Pascal M
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 01.01.2015
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201444707

Interleukin-1[beta] (IL-1[beta]) 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/CD16pos monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro-IL-1[beta] precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1[beta] are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL-1[beta]. The lack of secreted IL-1[beta] 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 P2×7 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[beta] 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[beta] 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.