Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

Abstract

Pre-pregnancy obesity is associated with several adverse maternal health outcomes, notably increased risk of infection as well as the incidence of gestational diabetes, preeclampsia, and preterm birth. However, the mechanisms by which pregravid obesity disrupts the pregnancy associated “immune clock” are still unknown. To address this question, we collected blood samples from women during the first and third trimesters and determined the impact of both pregnancy and pregravid obesity on circulating immune mediators, immune cell subset frequencies, and peripheral immune responses. While regardless of BMI, pregnancy was associated with an elevation in both Th1 and Th2 cytokines, pregravid obesity was associated with a dysregulation in circulating myeloid factors at term. Moreover, pregnancy in lean subjects was associated with enhanced monocyte activation, augmented chromatin accessibility at inflammatory loci, and heightened responses to LPS. Pregravid obesity disrupted this trajectory and was accompanied by a lack of transcriptional and epigenetic changes and alterations in metabolic status strongly suggesting a skewing towards immunotolerance. These findings provide novel insight into the increased susceptibility to infections observed with obesity during pregnancy.SUMMARYA healthy pregnancy is associated with progressive innate immune activation. Maternal factors such as obesity compromise this myeloid cell activation trajectory at genomic, epigenomic, functional, and metabolic levels, resulting in stagnant immune responses, suggestive of a state of tolerance.

Monocytes and macrophages in pregnancy: The good, the bad, and the ugly*

“…45 Specifically, the number of DEGs regulated by transcription factors IRF1, STAT1, and STAT3 were increased in T3 compared with T1. 45 Functional enrichment also F I G U R E 1 Changes in monocyte phenotype and function from the first to third trimester of pregnancy. Images were created using BioRender.com revealed a higher proportion of DEGs in T3 monocytes mapping to gene ontology (GO) terms associated with myeloid activation, leukocyte adhesion, and cytokine signaling in line with the enhanced anti-LPS response.…”

“…44 Furthermore, increased expression of HLA-DR, CD11a, CD49d, CD64, and CD54 has also been reported in circulating monocytes. 45 Comparison of T1 and T3 monocyte transcriptomes shows increased expression of MHC molecules (B2M and HLA-DRA) and pro-inflammatory genes (VCAN, LYZ) in late pregnancy. 45 Additionally, plasma levels of soluble CD14 (sCD14), a surrogate for in vivo monocyte activation, increased between T1 and T3.…”

“…45 Profiling transcriptional responses to LPS stimulation showed an increase in the number of differently expressed genes (DEG) between T1 and T3. 45 Specifically, the number of DEGs regulated by transcription factors IRF1, STAT1, and STAT3 were increased in T3 compared with T1. 45 Functional enrichment also F I G U R E 1 Changes in monocyte phenotype and function from the first to third trimester of pregnancy.…”

“…Images were created using BioRender.com revealed a higher proportion of DEGs in T3 monocytes mapping to gene ontology (GO) terms associated with myeloid activation, leukocyte adhesion, and cytokine signaling in line with the enhanced anti-LPS response. 45 Heightened monocyte activation and inflammatory responses to TLR stimulation are accompanied by increased chromatin accessibility between T1 and T3. 45 Indeed, epigenetic studies via ATAC-seq revealed a shift in accessible chromatin profiles in monocytes from T1 to T3, with significant increase in the accessibility of regions overlapping with promoters that regulate the expression of genes critical for leukocyte activation, myeloid differentiation, regulation of oxidative stress, and initiating inflammatory responses to lipids and TLR ligands.…”

“…45 Heightened monocyte activation and inflammatory responses to TLR stimulation are accompanied by increased chromatin accessibility between T1 and T3. 45 Indeed, epigenetic studies via ATAC-seq revealed a shift in accessible chromatin profiles in monocytes from T1 to T3, with significant increase in the accessibility of regions overlapping with promoters that regulate the expression of genes critical for leukocyte activation, myeloid differentiation, regulation of oxidative stress, and initiating inflammatory responses to lipids and TLR ligands. 45 In a healthy pregnancy, soluble factors such as placental microparticles, fetal cells, and cytokines activate circulating monocytes.…”