Abstract
The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, <28weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. DATABASES: EGAS00001003635 (EGA); PXD011626 (PRIDE).
Highlights
Intra-amniotic infection (IAI), one of the main causes of spontaneous preterm birth, can lead to a maternal (MIR) and a fetal (FIR) inflammatory response, which can be detected in placental tissues [1] (Table 1)
F2, FGA, FGB, and A1BG are secreted from the liver into the blood, and this may be the case for SERPINA3 and APOE, which have a biased expression toward the liver. These results show that in peripheral blood from extremely low gestational age newborn (ELGAN) there are sizable numbers of transcriptomic and proteomic changes associated with fetal inflammatory response (FIR) that can be detected in archived dried blood spot (DBS)
We found that the arginase 1 enzyme (ARG1) gene was 2.5-fold upregulated in FIR-affected ELGANs, as well as the OLR1 gene, encoding the lectin-type oxidized LDL receptor 1 (LOX1), a marker of G-myeloid-derived suppressor cell (MDSC) [17], which was over 10-fold upregulated
Summary
Intra-amniotic infection (IAI), one of the main causes of spontaneous preterm birth, can lead to a maternal (MIR) and a fetal (FIR) inflammatory response, which can be detected in placental tissues [1] (Table 1). FIR can damage the fetus presumably by triggering a local (e.g., lungs, skin) and systemic inflammation, which can lead to further distant organ injury, such as perinatal brain damage [2,3]. The molecular and cellular alterations induced by FIR persist after birth [6,7] and interact with postnatal inflammation-initiating illnesses [8]. This interaction leads to what is known as an intermittent or sustained systemic inflammation (ISSI) [9,10]. ISSI is strongly associated with perinatal brain injury and developmental disorders in ELGANs [10]
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