The Murine Amniotic Fluid Macrophage: Upregulation of Classical and Alternative Activation Markers Prior to Labor at Term
Montalbano, Alina Peraza
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The initiation of labor at term and preterm is associated with an inflammatory response, with increased interleukins in amniotic fluid (AF) and infiltration of the myometrium by neutrophils and macrophages (MΦ). Whereas, in preterm labor, intra-amniotic infection may provide the inflammatory stimulus for increased AF interleukins and inflammatory cell migration, the stimulus for these events at term has remained unclear. In studies using pregnant mice, we observed that the M that invade the maternal uterus near term originate from the fetus. Furthermore, we obtained compelling evidence that surfactant protein-A (SP-A), a developmentally regulated C-type lectin secreted by the fetal lung into AF near term, activates AF MΦ, which migrate into the pregnant uterus where their local release of interleukin-1 serves to activate nuclear factor kB (NF-kB) pathways. Activation of the NF-kB pathway results in increased expression of genes that promote uterine contractility and negatively impacts the capacity of progesterone receptors to maintain uterine quiescence, culminating in the onset of labor . We propose that interactions of MΦ surface receptors with SP-A, at term, or bacterial lipopolysaccharide at preterm, initiate changes in MΦ phenotypic properties, resulting in the enhanced expression of genes that promote MΦ migration to the uterus. The objectives of this study are: (1) to analyze the phenotypic changes of mouse AF MΦ associated with the developmental induction of SP-A synthesis and secretion by the fetal lung into AF: (2) to determine if SP-A, SP-D, and SP-A/D double deficiencies delay labor at term and to (3) to analyze trafficking patterns of fetal MΦ leading to the induction of labor. The findings presented herein suggest that late gestation AF MΦ upregulate classical and alternative activation markers in tandem as term approaches. Moreover, their phenotypic profile implies that they may modulate both pro- and anti-inflammatory functions simultaneously near term. Trafficking studies using heterozygous fetal-derived amniotic fluid macrophages expressing EGFP under control of the MΦ-specific CSF-1 receptor, demonstrate the absence of this subpopulation in the maternal uterus. Parturition studies in surfactant protein A and -D deficient mice reveal that deficiency in SP-A and –D does not affect the timing of labor. Intriguingly, Toll-like receptor 2 deficient mice demonstrate a delay in the time to parturition pointing to its potential role in mediating a signal for labor at term.