Impaired NLRP3 inflammasome activity during fetal development regulates IL-1ß production in human monocytes.
Eur J Immunol
; 45(1): 238-49, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25311115
ABSTRACT
Interleukin-1ß (IL-1ß) 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-1ß precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1ß are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL-1ß. The lack of secreted IL-1ß 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-1ß 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-1ß 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Monócitos
/
Proteínas de Transporte
/
Desenvolvimento Fetal
/
Interleucina-1beta
/
Inflamassomos
/
Macrófagos
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article