M1/M2 Macrophage Polarity in Normal and Complicated Pregnancy

Tissue macrophages play an important role in all stages of pregnancy, including uterine stromal remodeling (decidualization) before embryo implantation, parturition, and postpartum uterine involution. The activation state and function of utero-placental macrophages are largely dependent on the local tissue microenvironment. Thus, macrophages are involved in a variety of activities such as regulation of immune cell activities, placental cell invasion, angiogenesis, and tissue remodeling. Disruption of the uterine microenvironment, particularly during the early stages of pregnancy (decidualization, implantation, and placentation) can have profound effects on macrophage activity and subsequently impact pregnancy outcome. In this review, we will provide an overview of the temporal and spatial regulation of utero-placental macrophage activation during normal pregnancy in humans and rodents with a focus on more recent findings. We will also discuss the role of M1/M2 dysregulation within the intrauterine environment during adverse pregnancy outcomes

Host Genetic Background Impacts Disease Outcome During Intrauterine Infection with <em>Ureaplasma parvum</em>

<div><p><em>Ureaplasma parvum,</em> an opportunistic pathogen of the human urogenital tract, has been implicated in contributing to chorioamnionitis, fetal morbidity, and fetal mortality. It has been proposed that the host genetic background is a critical factor in adverse pregnancy outcome as sequela to <em>U. parvum</em> intra-amniotic infection. To test this hypothesis we assessed the impact of intrauterine <em>U. parvum</em> infection in the prototypical TH1/M1 C57BL/6 and TH2/M2 BALB/c mouse strain. Sterile medium or <em>U. parvum</em> was inoculated into each uterine horn and animals were evaluated for intra-amniotic infection, fetal infection, chorioamnionitis and fetal pathology at 72 hours post-inoculation. Disease outcome was assessed by microbial culture, <em>in situ</em> detection of <em>U. parvum</em> in fetal and utero-placental tissues, grading of chorioamnionitis, and placental gene expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9. Placental infection and colonization rates were equivalent in both strains. The <em>in situ</em> distribution of <em>U. parvum</em> in placental tissues was also similar. However, a significantly greater proportion of BALB/c fetuses were infected (P<0.02). C57BL/6 infected animals predominantly exhibited mild to moderate chorioamnionitis (P<0.0001), and a significant reduction in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 compared to sham controls (P<0.02). Conversely, severe protracted chorioamnionitis with cellular necrosis was the predominant lesion phenotype in BALB/c mice, which also exhibited a significant increase in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 (P<0.01). Fetal pathology in BALB/c was multi-organ and included brain, lung, heart, liver, and intestine, whereas fetal pathology in C57BL/6 was only detected in the liver and intestines. These results confirm that the host genetic background is a major determinant in ureaplasmal induced chorioamnionitis with fetal infection and fetal inflammatory response.</p> </div

Profiling of placental inflammatory mediators in sham inoculated BALB/c and C57BL/6 mice. (

<p>A) Normalized gene expression values are expressed as 2<i>⁻</i>^Δ<i>Ct</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044047#pone.0044047-Schmittgen1" target="_blank">[72]</a>. (B) Production of IL-10 expressed as mean (pg/gm weight of tissue) ± SD. Values represent 5 biological replicates from 3 independent experiments.</p

Predominant BALB/c and C57BL/6 response profile to <i>U. parvum</i> intrauterine infection.

<p>Predominant BALB/c and C57BL/6 response profile to <i>U. parvum</i> intrauterine infection.</p

Fetal inflammatory response criteria modified from Redline 2006 [32].

<p>Fetal inflammatory response criteria modified from Redline 2006 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044047#pone.0044047-Redline2" target="_blank">[32]</a>.</p

<i>In situ</i> detection of <i>U. parvum</i> in placental and fetal tissues.

<p>Representative 2D projection images (600 x magnifications) of placental choriodecidual junction (A), vitelline membrane (B), fetal intestine (C), and fetal lung (D). Scale bars are equivalent to 100 µm. <i>U. parvum</i> (red) was initially labeled with rabbit polyclonal antibody as previously described <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044047#pone.0044047-Reyes2" target="_blank">[69]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044047#pone.0044047-Allam1" target="_blank">[71]</a>. Cell nuclei (blue) were labeled with DAPI. Long arrows (A and B) are highlighting <i>U. parvum</i> engulfed by polymorphonuclear cells. Block arrows (D and E) are highlighting epicellular <i>U. parvum</i>.</p

Placental inflammatory profiles in <i>U. parvum</i> infected BALB/c and C57BL/6 mice. (

<p>A) Fold change (2<i>⁻</i>^{ΔΔ<i>Ct</i>} ) is relative to normalized Ct values from sham inoculated controls, which was determined by the method of Schmittgen and Livak <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044047#pone.0044047-Schmittgen1" target="_blank">[72]</a>. Values represent the mean 2<i>⁻</i>^{ΔΔ<i>Ct</i>} ± SD of 5 biological replicates from 3 independent experiments.* Indicates a significant difference (P<0.01), which was determined by Student’s t test using 2<i>⁻</i>^Δ<i>Ct</i> data. (B) Mean IL-10± SD expressed as pg/gm weight of tissue of 5 biological replicates from 3 independent experiments. ** Indicates a significant difference (P<0.03).</p

Lesion scoring criteria for maternal inflammatory response [32].

<p>Lesion scoring criteria for maternal inflammatory response <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044047#pone.0044047-Redline2" target="_blank">[32]</a>.</p

Representative images of metritis.

<p>Sham inoculated (Control) and representative lesions in <i>U. parvum</i> infected C57BL/6 mice (B, mild metritis) and in <i>U. parvum</i> infected BALB/c mice (C and D, more extensive metritis). Scale bars are equivalent to 100 µm. Arrows are highlighting neutrophilic infiltrates.</p