title: Impaired NLRP3 inflammasome activity during fetal development regulates IL-1β production in human monocytes.
abstract: Interleukin-1β (IL-1β) 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-1β precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1β are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL-1β. The lack of secreted IL-1β 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-1β 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-1β 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.
authors.affiliation: Child & Family Research Institute, Vancouver, BC, Canada; Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ashish A
authors.initials: AA
authors.lastname: Sharma
authors.forename: Roger
authors.initials: R
authors.lastname: Jen
authors.forename: Bernard
authors.initials: B
authors.lastname: Kan
authors.forename: Abhinav
authors.initials: A
authors.lastname: Sharma
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Marchant
authors.forename: Anthony
authors.initials: A
authors.lastname: Tang
authors.forename: Izabelle
authors.initials: I
authors.lastname: Gadawski
authors.forename: Christof
authors.initials: C
authors.lastname: Senger
authors.forename: Amanda
authors.initials: A
authors.lastname: Skoll
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sly
authors.forename: Hélène C F
authors.initials: HC
authors.lastname: Côté
authors.forename: Pascal M
authors.initials: PM
authors.lastname: Lavoie
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D047109:Fetal Development / Q000276:immunology*; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D058486:Receptors, Purinergic P2X7; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate
keywords: Human; Inflammasome; Interleukin-1 beta (IL-1β); Neonate; Toll-like receptor