The Implication of Aberrant GM-CSF Expression in Decidual Cells in the Pathogenesis of Preeclampsia

Abstract

Preeclampsia is characterized by an exaggerated systemic inflammatory state as well as shallow placentation. In the decidual implantation site , preeclampsia is accompanied by an excessive number of both macrophages and dendritic cells as well as their recruiting chemokines, which have been implicated in the impairment of endovascular trophoblast invasion. Granulocyte-macrophage colony-stimulating factor is known to regulate the differentiation of both macrophages and dendritic cells, prompting both in vivo and in vitro evaluation of granulocyte-macrophage colony-stimulating factor expression in human decidua as well as in a mouse model of preeclampsia. This study revealed increased granulocyte-macrophage colony-stimulating factor expression levels in preeclamptic decidua. Moreover, both tumor necrosis factor-␣ and interleukin-1 ␤, cytokines that are implicated in the genesis of preeclampsia, markedly up-regulated granulocyte-macrophage colony-stimulating factor production in cultured first-trimester human decidual cells. The conditioned media of these cultures promoted the differentiation of both macrophages and dendritic cells from a monocyte precursor. Evaluation of a murine model of preeclampsia revealed that the decidua of affected animals displayed higher levels of immunoreactive granulocyte-macrophage colony-stimulating factor as well as increased numbers of both macrophages and dendritic cells when compared to control animals. Because granulocyte-macrophage colony-stimulating factor is a potent inducer of differentiation and activation of both macrophages and dendritic cells , these findings suggest that this factor plays a crucial role in the pathogenesis of preeclampsia. (Am J

Macrophages at the Fetal–Maternal Interface Express Markers of Alternative Activation and Are Induced by M-CSF and IL-10

“…Accordingly, increased local and circulating GM-CSF levels have been associated with preeclampsia, an inflammatory placenta disorder (65,66), although other reports failed to demonstrate such associations (67,68). Our results suggest that the balance between M-CSF and GM-CSF at the fetal-maternal interface needs to be strictly regulated, which might be done, at least in part, by progesterone, which has been shown to upregulate M-CSF and downregulate GM-CSF (53,69).…”

The Placenta in Toxicology. Part II

“…However, the findings of elevated decidual granulocyte-macrophage colony-stimulating factor (GM-CSF levels; Huang et al 2010), and reduced decidual and placental IL-10 in preeclamptic patients (Hennessy et al 1999;Schonkeren et al 2011) are consistent with decreased numbers of regulatory CD163 þ macrophages in preeclamptic deciduas (Schonkeren et al 2011). These data implicate a defect M2 macrophage polarization in the development of preeclampsia, and support a role for IL-10 in promoting, and for GM-CSF in counteracting, the induction of homeostatic decidual macrophages (Svensson et al 2011).…”

Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

“…Thus, we suggest that M-CSF and IL-10 promote homeostatic M2 macrophages that are able to protect the fetus against invading pathogens without compromising fetal survival. In addition, increased decidual GM-CSF levels (Huang et al, 2010), and reduced decidual and placental IL-10 have been described in preeclamptic patients (Hennessy et al, 1999;Schonkeren et al, 2011).…”

“…Several studies have analyzed the concentrations of these factors, especially GM-CSF, in pregnancy complications, however with inconsistent results (Greer et al, 1994;Gratacos et al, 1998;Hayashi et al, 2004;Huang et al, 2010;Boij et al, 2012). Given their dose-dependent and differential effects on macrophage polarization, studying the levels of M-CSF and GM-CSF in relation to each other, rather than analyzing them separately, should be more informative.…”

“…Thus, the role of decidual macrophages in the development of complications is likely to be more related to the function of macrophages (or a combination of the both). Indeed, some studies have reported altered expression of M2 macrophage markers (for instance CD163, CD206 and CD209) (Schonkeren et al, 2011;Hsu et al, 2012;Prins et al, 2012) or production of factors influencing macrophage polarization (for instance GM-CSF and IL-10) (Hennessy et al, 1999;Huang et al, 2010;Schonkeren et al, 2011) in pregnancy complications. However, evidence is still scarce, partly reflecting the limited information about decidual macrophage function during healthy pregnancy.…”