Pre‐eclampsia is associated with dendritic cell recruitment into the uterine decidua

Abstract

Pre-eclampsia is a leading cause of fetal and maternal morbidity and mortality that preferentially affects primiparous patients. It is associated with systemic inflammation and impaired trophoblast invasion of the decidua. Decidual cells are the major cell type of the pregnant endometrium. Macrophages and dendritic cells are major specialized antigen-presenting cells that promote both innate immunity and immune tolerance. Macrophage infiltration is implicated in impaired trophoblast invasion that leads to pre-eclampsia. By contrast, the potential modulating role of decidual dendritic cells in the genesis of pre-eclampsia has not been investigated. Interleukin-1beta (IL-1beta), a pro-inflammatory cytokine, has been implicated in the genesis of pre-eclampsia. Thus, we postulate that pre-eclampsia would be associated with enhanced decidual dendritic cells infiltration and that IL-1beta would enhance the production of relevant dendritic cell-recruiting chemokines. We used immunohistochemistry to demonstrate a marked infiltrate of immature and mature dendritic cells in pre-eclamptic decidua. Further, immunohistochemistry and immunoassays of placental bed biopsies revealed that pre-eclamptic decidua displays elevated levels of several monocyte- and dendritic cell-recruiting chemokines. Leukocyte-free first-trimester decidual cells were then treated with IL-1beta, which enhanced the mRNA and protein expression of these chemokines. The current study also confirmed previous reports that macrophages directly impaired trophoblast invasion and that this inhibitory effect is augmented by the conditioned medium of IL-1beta-treated first-trimester decidual cells. However, unlike macrophages, dendritic cells did not directly impede trophoblast invasion. This study demonstrates that the inflammatory milieu of pre-eclampsia induces decidual cells to promote dendritic cell infiltration. Given their unusual versatility in mediating both immunity and tolerance, these novel findings suggest that dendritic cells may play a critical role either in the pathogenesis of pre-eclampsia or its prevention in subsequent pregnancies.

Immune cells in the placental bed

“…Increased numbers of both CD209+ immature dendritic cells and mature CD83+ activated dendritic cells have been reported but whether this is a cause or effect of this condition is unclear (Huang et al, 2008). In contrast, Scholz et al (2008) reported no difference in numbers of DC-SIGN+ (CD209+) or DEC-205 in term decidual tissue (attached to the delivered placenta) from women with pre-eclampsia and fetal growth restriction compared to age matched controls.…”

“…However, non-activated macrophages had no effect on trophoblast invasion. In addition, Huang et al (2008) also demonstrated that macrophages derived from the THP-1 cell line inhibited HTR-8/SVneo invasion although a mechanism was not investigated.…”

“…In vitro functional experiments performed with dendritic like cells derived from the THP-1 cell line suggest that dendritic cells have no effect of trophoblast invasion (Huang et al, 2008). In addition, while isolated decidual immature CD14+DC-SIGN+ dendritic cells were able to mature into CD25+CD83+ mature dendritic cells and take up antigen, they were not able to stimulate naïve allogeneic T cells (Kammerer et al, 2003).…”

Immunological role of vitamin D at the maternal–fetal interface

“…In studies of recurrent PET (Huang et al 2008), and recurrent miscarriage (Askelund et al 2004), an overabundance of decidual DCs has been observed, suggesting that DCs may be involved in the aetiology of some adverse events in pregnancy. The presence of an active intracrine system for vitamin D in DCs strongly suggests that variations in maternal 25OHD may have a significant effect on DC recruitment, maturation and antigen presentation.…”

“…In future studies, it will be important to assess the impact of vitamin D status on decidual DC function. However, in addressing this, it is unclear how effective animal models will be, given that mice lacking uterine DCs do not show obvious reproductive deficits (Huang et al 2008).…”