AUTHOR=Zarate Miguel A. , De Dios Robyn K. , Balasubramaniyan Durganili , Zheng Lijun , Sherlock Laura G. , Rozance Paul J. , Wright Clyde J. 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.706774

DOI=10.3389/fimmu.2021.706774

ISSN=1664-3224

ABSTRACT=<p>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 (<italic>Nfkbia</italic> and <italic>Nfkbib</italic>) and the NF-κB subunit <italic>Nfkb1</italic> in IUGR <italic>vs.</italic> NG. We next measured the LPS-induced hepatic expression of acute proinflammatory genes (<italic>Ccl3</italic>, <italic>Cxcl1</italic>, <italic>Il1b</italic>, <italic>Il6</italic>, and <italic>Tnf</italic>) and observed that the IUGR liver produced an attenuated acute proinflammatory cytokine gene response (<italic>Il1b and Tnf</italic>) to LPS in IUGR <italic>vs.</italic> unexposed (CTR). Consistent with these results, LPS-exposed hepatic tumor necrosis factor alpha (TNF-α) protein concentrations were lower in IUGR <italic>vs.</italic> LPS-exposed NG and did not differ from IUGR CTR. Sex differences at the transcriptome level were observed in the IUGR male <italic>vs.</italic> 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.</p>