Dataset Information

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

ABSTRACT: 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 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? 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.

SUBMITTER: Sharma AA

PROVIDER: S-EPMC4619041 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Sharma Ashish A AA Jen Roger R Kan Bernard B Sharma Abhinav A Marchant Elizabeth E Tang Anthony A Gadawski Izabelle I Senger Christof C Skoll Amanda A Turvey Stuart E SE Sly Laura M LM Côté Hélène C F HC Lavoie Pascal M PM

European journal of immunology 20141117 1

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 leve ...[more]

PMID: 25311115

Similar Datasets

Project description:BackgroundInterleukin-1? (IL-1?) is one of the most important cytokine secreted by activated microglia as it orchestrates the vicious cycle of inflammation by inducing the expression of various other pro-inflammatory cytokines along with its own production. Microglia-mediated IL-1? production is a tightly regulated mechanism which involves the activation of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome pathway. Our previous study suggests the critical role of heat shock protein 60 (HSP60) in IL-1?-induced inflammation in microglia through TLR4-p38 MAPK axis. However, whether HSP60 regulates endogenous IL-1? production is not known. Therefore, to probe the underlying mechanism, we elucidate the role of HSP60 in endogenous IL-1? production.MethodsWe used in vitro (N9 murine microglial cells) and in vivo (BALB/c mouse) models for our study. HSP60 overexpression and knockdown experiment was done to elucidate the role of HSP60 in endogenous IL-1? production by microglia. Western blotting and quantitative real-time PCR was performed using N9 cells and BALB/c mice brain, to analyze various proteins and transcript levels. Reactive oxygen species levels and mitochondrial membrane depolarization in N9 cells were analyzed by flow cytometry. We also performed caspase-1 activity assay and enzyme-linked immunosorbent assay to assess caspase-1 activity and IL-1? production, respectively.ResultsHSP60 induces the phosphorylation and nuclear localization of NF-?B both in vitro and in vivo. It also induces perturbation in mitochondrial membrane potential and enhances reactive oxygen species (ROS) generation in microglia. HSP60 further activates NLRP3 inflammasome by elevating NLRP3 expression both at RNA and protein levels. Furthermore, HSP60 enhances caspase-1 activity and increases IL-1? secretion by microglia. Knockdown of HSP60 reduces the IL-1?-induced production of IL-1? both in vitro and in vivo. Also, we have shown for the first time that knockdown of HSP60 leads to decreased IL-1? production during Japanese encephalitis virus (JEV) infection, which eventually leads to decreased inflammation and increased survival of JEV-infected mice.ConclusionHSP60 mediates microglial IL-1? production by regulating NLRP3 inflammasome pathway and reduction of HSP60 leads to reduction of inflammation in JEV infection.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets