Cargando…

The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice

Intrauterine growth restriction (IUGR) is a relevant predictor for higher rates of neonatal sepsis worldwide and is associated with an impaired neonatal immunity and lower immune cell counts. During the perinatal period, the liver is a key immunological organ responsible for the nuclear factor kappa...

Descripción completa

Detalles Bibliográficos
Autores principales: Zarate, Miguel A., De Dios, Robyn K., Balasubramaniyan, Durganili, Zheng, Lijun, Sherlock, Laura G., Rozance, Paul J., Wright, Clyde J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440955/
https://www.ncbi.nlm.nih.gov/pubmed/34539638
http://dx.doi.org/10.3389/fimmu.2021.706774
_version_ 1783752776052899840
author Zarate, Miguel A.
De Dios, Robyn K.
Balasubramaniyan, Durganili
Zheng, Lijun
Sherlock, Laura G.
Rozance, Paul J.
Wright, Clyde J.
author_facet Zarate, Miguel A.
De Dios, Robyn K.
Balasubramaniyan, Durganili
Zheng, Lijun
Sherlock, Laura G.
Rozance, Paul J.
Wright, Clyde J.
author_sort Zarate, Miguel A.
collection PubMed
description Intrauterine growth restriction (IUGR) is a relevant predictor for higher rates of neonatal sepsis worldwide and is associated with an impaired neonatal immunity and lower immune cell counts. During the perinatal period, the liver is a key immunological organ responsible for the nuclear factor kappa B (NF-κB)-mediated innate immune response to inflammatory stimuli, but whether this role is affected by IUGR is unknown. Herein, we hypothesized that the newborn liver adapts to calorie-restriction IUGR by inducing changes in the NF-κB signaling transcriptome, leading to an attenuated acute proinflammatory response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic gene expression of key NF-κB factors in the IUGR and normally grown (NG) newborn mice. Real-time quantitative PCR (RT-qPCR) analysis revealed an upregulation of both IκB proteins genes (Nfkbia and Nfkbib) and the NF-κB subunit Nfkb1 in IUGR vs. NG. We next measured the LPS-induced hepatic expression of acute proinflammatory genes (Ccl3, Cxcl1, Il1b, Il6, and Tnf) and observed that the IUGR liver produced an attenuated acute proinflammatory cytokine gene response (Il1b and Tnf) to LPS in IUGR vs. unexposed (CTR). Consistent with these results, LPS-exposed hepatic tumor necrosis factor alpha (TNF-α) protein concentrations were lower in IUGR vs. LPS-exposed NG and did not differ from IUGR CTR. Sex differences at the transcriptome level were observed in the IUGR male vs. female. Our results demonstrate that IUGR induces key modifications in the NF-κB transcriptomic machinery in the newborn that compromised the acute proinflammatory cytokine gene and protein response to LPS. Our results bring novel insights in understanding how the IUGR newborn is immunocompromised due to fundamental changes in NF-κB key factors.
format Online
Article
Text
id pubmed-8440955
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-84409552021-09-16 The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice Zarate, Miguel A. De Dios, Robyn K. Balasubramaniyan, Durganili Zheng, Lijun Sherlock, Laura G. Rozance, Paul J. Wright, Clyde J. Front Immunol Immunology Intrauterine growth restriction (IUGR) is a relevant predictor for higher rates of neonatal sepsis worldwide and is associated with an impaired neonatal immunity and lower immune cell counts. During the perinatal period, the liver is a key immunological organ responsible for the nuclear factor kappa B (NF-κB)-mediated innate immune response to inflammatory stimuli, but whether this role is affected by IUGR is unknown. Herein, we hypothesized that the newborn liver adapts to calorie-restriction IUGR by inducing changes in the NF-κB signaling transcriptome, leading to an attenuated acute proinflammatory response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic gene expression of key NF-κB factors in the IUGR and normally grown (NG) newborn mice. Real-time quantitative PCR (RT-qPCR) analysis revealed an upregulation of both IκB proteins genes (Nfkbia and Nfkbib) and the NF-κB subunit Nfkb1 in IUGR vs. NG. We next measured the LPS-induced hepatic expression of acute proinflammatory genes (Ccl3, Cxcl1, Il1b, Il6, and Tnf) and observed that the IUGR liver produced an attenuated acute proinflammatory cytokine gene response (Il1b and Tnf) to LPS in IUGR vs. unexposed (CTR). Consistent with these results, LPS-exposed hepatic tumor necrosis factor alpha (TNF-α) protein concentrations were lower in IUGR vs. LPS-exposed NG and did not differ from IUGR CTR. Sex differences at the transcriptome level were observed in the IUGR male vs. female. Our results demonstrate that IUGR induces key modifications in the NF-κB transcriptomic machinery in the newborn that compromised the acute proinflammatory cytokine gene and protein response to LPS. Our results bring novel insights in understanding how the IUGR newborn is immunocompromised due to fundamental changes in NF-κB key factors. Frontiers Media S.A. 2021-09-01 /pmc/articles/PMC8440955/ /pubmed/34539638 http://dx.doi.org/10.3389/fimmu.2021.706774 Text en Copyright © 2021 Zarate, De Dios, Balasubramaniyan, Zheng, Sherlock, Rozance and Wright https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zarate, Miguel A.
De Dios, Robyn K.
Balasubramaniyan, Durganili
Zheng, Lijun
Sherlock, Laura G.
Rozance, Paul J.
Wright, Clyde J.
The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice
title The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice
title_full The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice
title_fullStr The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice
title_full_unstemmed The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice
title_short The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice
title_sort acute hepatic nf-κb-mediated proinflammatory response to endotoxemia is attenuated in intrauterine growth-restricted newborn mice
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440955/
https://www.ncbi.nlm.nih.gov/pubmed/34539638
http://dx.doi.org/10.3389/fimmu.2021.706774
work_keys_str_mv AT zaratemiguela theacutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT dediosrobynk theacutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT balasubramaniyandurganili theacutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT zhenglijun theacutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT sherlocklaurag theacutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT rozancepaulj theacutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT wrightclydej theacutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT zaratemiguela acutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT dediosrobynk acutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT balasubramaniyandurganili acutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT zhenglijun acutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT sherlocklaurag acutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT rozancepaulj acutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice
AT wrightclydej acutehepaticnfkbmediatedproinflammatoryresponsetoendotoxemiaisattenuatedinintrauterinegrowthrestrictednewbornmice