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We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Preeclampsia is an important complication in pregnancy, characterized by hypertension and proteinuria in the second half of pregnancy. Preeclampsia is one of the leading complications of pregnancy, characterized by hypertension and proteinuria and developing in the second half of pregnancy (1, 2).
During normal pregnancy, the circulation of peripheral blood through the placenta results in direct or indirect contact of maternal immune cells with the placenta. At the maternal–fetal interface, from the beginning of a healthy pregnancy, there is an increase of innate immune cells, such as macrophages and NK cells (10). Monocytes and macrophages may thus play an important role in healthy pregnancy as well in the pathophysiology of pre-eclampsia.
Monocytes arise from precursors in the bone marrow and comprise about 5–10% of the circulating blood leukocytes. Macrophages are located in all body tissues, where they are important in detecting, ingesting, and processing foreign material, dead cells, and other debris (12). There is debate on the fate of the different monocyte subsets; it is unclear whether tissue macrophages are derived from a specific monocyte subset or from either subset randomly (12).
During normal pregnancy, the female immune system has to adapt to the presence of the semi-allogeneic fetus. Although it has been known for a long time that leukocyte numbers increase during pregnancy, at that time this was not recognized as a sign of generalized inflammation in pregnant women. In the studies presented above, monocytes have been characterized by CD14 expression, indicating that mainly classical monocytes have been studied in pregnancy. It has now been well-established that during pre-eclampsia, the innate immune system is even further activated as compared with normal pregnancy (50). The exact mechanisms involved in the activation of monocytes during pregnancy and pre-eclampsia remain unknown.
It appears to be important for induction of pre-eclamptic signs how monocytes are activated. Although it is now generally accepted that during pregnancy monocytes are activated and that they are even further activated during pre-eclampsia, whether this is the cause or consequence of pre-eclampsia still remains to be shown. Various rat models have suggested that activation of monocytes, by LPS, ATP, or TNFα during pregnancy, induced pre-eclampsia-like signs (70, 77, 78). Based on the above data on monocytes during pregnancy and pre-eclampsia, we suggest that factors that arise from the healthy placenta during pregnancy induce phenotypical activation of monocytes and induce increased maturation toward non-classical monocytes.
Macrophages are already present in the non-pregnant endometrium, although in low numbers (81). Macrophages are present in the decidua throughout pregnancy until the end of pregnancy, although their numbers may decrease at the end of pregnancy (88). Preeclampsia is associated with defective trophoblast invasion and spiral artery remodeling: while in healthy pregnancy, spiral artery remodeling extends into the myometrium, in pre-eclampsia, spiral artery remodeling can only be found in the decidua (3). Not surprisingly, many of the pregnancy-related disorders such as recurrent miscarriages and pre-eclampsia are thought to be due to the breakdown of this immune tolerance (6, 9, 10). In this review, we will explore the role of decidual innate and the adaptive immune cells in facilitating tolerance to the fetus.
Antigen presenting cells are likely to be important players in the mediation of immune tolerance in the decidua. Study of decidual dendritic cells (dDCs) has been difficult, not only because isolation of decidual cells including dDCs can be technically demanding, but also because phenotypic definition of DCs is controversial as there is no single specific marker for DCs.
Overall, due to the difficulty in decidual mononuclear cell isolation and the rarity of dDCs, functional studies on these DCs are scarce. Macrophages are specialized phagocytic cells of the innate immune system and they are present in every organ of the body in one form or another. Dendritic cell specific ICAM3 grabbing non-integrin is an ICAM3 receptor, where ICAM3 is an adhesion molecule.
Decidual NK cells (dNK) are the most abundant maternal leukocytes in the decidua, especially in the first trimester, making up 70% of the maternal CD45+ leukocyte population.
Decidual NK cells may also be important in modulating the degree of trophoblast invasion, as they are seen in close proximity to the invading trophoblasts in the decidua. Collectively, these data suggest that dNK cells are important for modulation of trophoblast invasion and decidual vascularization in pregnancy.
The adaptive immune system distinguishes itself from the innate immune system by its antigen specificity and immunological memory. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience.
Generalized activation of the inflammatory response is thought to play a role in the pathogenesis of pre-eclampsia. Preeclampsia is suggested to be a two stage disease: the first stage being poor placentation (3). These macrophages and NK cells may have a local immune function, however, they also appear to be important for placental development by promoting trophoblast recruitment, spiral artery remodeling, and angiogenesis (11). Further insight into the role of these cells in these conditions, may lead to a better understating of the inflammatory response in normal pregnancy and in pre-eclampsia. They circulate in the blood for a few days before migrating into tissues to become macrophages or dendritic cells (12). Monocytes are macrophage precursors (12); monocytes can be recruited into tissues, to replenish steady state macrophages or can be recruited in inflammatory conditions (12), where they mature into macrophages (or dendritic cells) (12).
It has been suggested that classical monocytes preferentially differentiate into M1 macrophages, while the non-classical monocytes preferentially differentiate into M2 macrophages during inflammation (20). Many changes in the peripheral circulation have been observed, both in the specific and innate immune response. With the introduction of new techniques, most importantly, flow cytometry, function and activation status of leukocytes monocyte could be examined by measuring expression of markers of activation and production of intracellular cytokines. This has, for instance, been demonstrated by measuring the production of oxygen free radicals (32), which is increased in pregnant women.
Recently, we conducted a study in which we identified the three subtypes of monocytes in pregnant women (41).
At the end of gestation, the number of leukocytes in the uterine tissue are increased (46). Activation of monocytes has been demonstrated by increased expression of inflammation associated adhesion molecules such as CD11b, ICAM-1, and CD14 (5, 32, 51, 52). Factors may be derived from the stressed placenta, such as anti-angiogenic factors (61), placental microparticles (62), or ATP (9), which are released at increased amounts from the pre-eclamptic placenta. In pregnant rats, hypertension and proteinuria can only be induced after infusion with E coli LPS (70), not after infusion of LPS from Porphyromonas gingivalis (71), despite the fact that monocytes are activated by this LPS (72).
It is difficult to study the role of monocytes in pregnancy and pre-eclampsia in human subjects. Interestingly, such pre-eclampsia-like syndromes were only induced in pregnant rats, not in non-pregnant rats (70, 77). Schematic overview of the role of monocytes during healthy pregnancy (A) and pre-eclampsia (B). Since their numbers fluctuate during the menstrual cycle (81, 82), it seems likely that these are under hormonal control (83).
At this time of pregnancy, macrophages are located near the spiral arteries during trophoblast invasion and spiral artery remodeling (86, 89). Although they express many markers of M2 macrophages, such as CD206, CD163, and DC-sign (100–102), they appeared not to be typical M2 macrophages, since they are not induced by Th2 cytokines, such as IL4, but by M-CSF and IL-10 (102). Decidual macrophages have been shown to express inhibitory receptors immunoglobulin like transcript (ILT)2 and ILT4 (108).
The exact role of decidual macrophages at the end of pregnancy remains to be established, it seems, however, likely that they are still involved in immunoregulation and clearance of apoptotic cells. Unfortunately, not very many studies focused on macrophages in the decidua in pre-eclampsia. In humans, the maternal immune system must tolerate the semi-allogeneic fetus throughout the 9 months of pregnancy.
Indeed, it is now well-known that fetal cells are largely separated from the maternal immune system, with the point of contact being fetal extravillous trophoblast (EVT) cells, which have poor antigenic properties owing to the lack of expression of classical MHC class I (except HLA-C) and MHC class II molecules (2).
In pre-eclampsia, whilst the clinical manifestations such as hypertension and proteinuria are thought to be due to endotheliopathy secondary to insufficient placentation (11, 12), the shallow fetal trophoblast invasion is likely related to partial breakdown of maternal–fetal immune tolerance (9).
In particular, we will highlight some of the recent advances documenting the interaction between these cells, drawing comparisons between healthy human pregnancy and pre-eclampsia. In this particular section, we refer primarily to the lineage negative HLA-DR+ classical DCs. Selective ablation of CD11c+ decidual DCs leads to failure of decidualization and embryo implantation (18), highlighting the potential role of dDCs in the initiation of successful pregnancy. Macrophages, like DCs, are part of the mononuclear phagocyte system consisting of committed bone marrow precursors, peripheral blood monocytes and DCs, as well as tissue macrophages and DCs (24).
DC-SIGN, also known as CD209, is important for the initiation of DC and T cell interaction (39). We speculate that this phenotypic difference may be related to the reduced placental IL-10 levels in pre-eclamptic pregnancies (47). Their potential relationships and differences in healthy pregnancy and pre-eclampsia are summarized in Figure 1.
However, the recognition and tolerance of paternal allo-antigens via APC presentation during pregnancy, clearly requires the participation of other limbs of the immune system, such as the adaptive immune cells.
Therefore, the fact that pre-eclampsia is essentially a disease of primigravida and subsequent pregnancies with the same partner protect against pre-eclampsia (58, 59), supports the involvement of the adaptive immune system. Several authors have shown that in pregnancy, there is an expansion of peripheral blood Treg cell pool in both humans (68, 69) and mice (70).
The second stage is the production of pro-inflammatory factors by the diseased placenta, which activates the systemic inflammatory response, leading to the signs of pre-eclampsia (3). In pre-eclampsia, due to production of pro-inflammatory factors from the placenta (6–9), monocytes are even further activated and together with activation of other inflammatory cells, such as granulocytes and endothelial cells, finally induce the full blown syndrome of pre-eclampsia (3). Therefore, the present paper will review the systemic and local changes in the decidua in monocytes and macrophages and their subsets during healthy human pregnancy and pre-eclampsia. Macrophages play an important role in the innate and adaptive immune responses to pathogens and are important mediators of inflammatory processes (12).
However, various studies have shown that such a strict distinction between differentiation of classical and non-classical monocytes may not be very likely and that it may depend on the model and the inflammatory stimulus whether a monocyte differentiates into an M1 or M2 macrophage (20, 21). Moreover, the flow cytometric analysis did not require isolation of cells from whole blood, as measurements could be done in whole blood.


Although some authors have shown increased cytokine production by non-stimulated monocytes from pregnant women vs. We showed a decreased number of classical monocytes and an increased number of intermediate monocytes in healthy pregnancy.
Also in the peripheral circulation just before delivery, further phenotypical activation of monocytes in comparison with earlier in pregnancy has been shown (47), indicating further activation of these cells just before delivery. However, monocytes are not only phenotypically activated, they also produced increased amounts of oxygen free radicals as compared to normal pregnancy (32) and their cytokine production also differed as compared to monocytes from normal pregnant women (38, 53–56). Peripheral monocytes circulate through the placental circulation and come into close contact with the semi-allogeneic villous syncytiotrophoblast (Figure 1). This may explain why certain infections, such as urinary tract infections or periodontitis, may increase the risk of pre-eclampsia, while other infections, such as CMV or malaria do not increase the risk for pre-eclampsia (73).
The pathophysiology of the LPS and ATP induced pre-eclampsia was characterized by a pregnancy-specific inflammatory response, characterized by persistent general (75, 76, 79) and glomerular (79, 80) inflammation, in which monocytes play a major role.
During pre-eclampsia, the stressed placenta starts to produce various pro-inflammatory factors, which further activate the monocytes and further increased monocyte maturation toward non-classical monocytes.
During healthy pregnancy, placental factors (1) activate monocytes (2) and may affect endothelial cells (2) and induce increased maturation of classical monocytes toward non-classical monocytes (3).
After fertilization, the number of uterine macrophages increase, due to expression of various chemokines (84) and during pregnancy macrophages are abundantly present in the decidua at all times of pregnancy (85).
The role of macrophages in spiral artery remodeling was further emphasized by the fact that they are present even before the presence of extravillous trophoblast (93). These data are in line with the abundant presence of M-CSF and IL-10 in the decidua (103–105).
These receptors can bind to HLA-G expressed on invading extravillous trophoblast (108), after which a negative signal is delivered to the macrophages, resulting in tolerance to the trophoblast and the induction of anti-inflammatory cytokines. Indeed, many of the macrophages present in the decidua at the end of pregnancy, appeared to be M2 macrophages (112). Most of the studies in pre-eclampsia were obviously performed after delivery of the placenta. Indeed, many lines of evidence suggest an immunological origin to the common pregnancy-related disorder, pre-eclampsia. The remarkable nature of this phenomenon was recognized by Peter Medawar in the 1950s (1), whose work on skin graft rejection in genetically different individuals, led him to perceive this apparent immunological paradox. However, as fetal–maternal microchimerism is a well-recognized occurrence during human pregnancy, fetal cells frequently induce maternal immune activation (3, 4) as evidenced by the detection of anti-fetal HLA antibodies in maternal serum during pregnancy (5, 6). As the major histocompatibility antigens (classical MHC I and II antigens) are suppressed on fetal trophoblast cells to evade maternal immune recognition, antigen presentation of fetal minor histocompatibility antigens by maternal APCs is an important route for immune recognition (7). Using lineage negative and HLA-DR+ as combination marker for dendritic cell (DC), Gardener et al. They went on to show that the CD83+ cells are potent stimulators in mixed lymphocyte reactions comparable to mature peripheral blood monocyte-derived DCs.
Another study demonstrated that during murine pregnancy, decidual CD11c+ DCs fail to migrate to draining lymph nodes due to absent lymphatic vessels and CCL21 (ligand for lymphoid homing CCR7) expression in the murine decidua and therefore do not significantly contribute to anti-fetal T cell responses (19).
Whilst many have attempted to separate macrophages from DCs based on phenotype and function, significant controversy exists as to whether these cells are indeed distinct from one another (25). They did not find any difference in HLA-DR, dendritic cell specific intercellular adhesion molecule 3 (ICAM3) grabbing non-integrin (DC-SIGN), or CD14 expression within CD45+ cells between healthy pregnancy and pre-eclampsia.
The origin of these cells is unclear, although some have proposed possible recruitment of a subset of peripheral blood CD56hi NK cells into the decidua (49).
The HLA-C–KIR interaction is thought to be important in the pathogenesis of pre-eclampsia.
Monocytes are short lived cells that mature in the circulation and invade into tissues upon an inflammatory stimulus and develop into macrophages. It has recently become clear that circulating monocytes are a heterogeneous population (12).
However, they also have anti-inflammatory properties, as they are also involved in the resolution of the inflammation (12).
These changes may be associated with changes in regulatory T cells (26, 27) and Th17 cells (27). This represents the in vivo situation much better, since isolation of leukocytes from blood may activate these cells (31). These results are in line with the suggestion that pregnancy is an inflammatory condition, since in other inflammatory diseases, this intermediate subset has also been shown to be increased (42, 43).
As for normal pregnancy, the above mentioned studies did not take into account the presence of monocyte subsets and monocytes are generally defined as CD14 positive. In the fetal part of the placenta, chorionic villi, covered with syncytiotrophoblast, bath in maternal blood of the intervillous space. Apparently, the immune response, and specifically monocyte activation is different in different infections.
In the ATP model, we have shown that, similar to human pre-eclampsia, non-classical monocytes are increased and activated by ATP, suggesting an important role for this subset in pre-eclampsia. During pre-eclampsia, more and other soluble factors are produced from the stressed placenta (1), resulting in further activation of monocytes and endothelial cells (2) and further maturation of classical monocytes toward non-classical monocytes (3). At that time, disruption and disorganization of vascular smooth muscle cells and endothelial cells was also observed (93).
The M2 phenotype is most likely due to hypermethylation of genes encoding markers of classical activation and hypomethylation of genes encoding markers for non-classical activation (106).
It has also been suggested that the engulfment of the apoptotic cells induced an immunosuppressive and anti-inflammatory phenotype of the macrophages (97). The potential protective effect of M2 macrophages for the fetus was recently shown by van Schonkeren et al., who showed the presence of an inflammatory lesion in placentae from women who underwent egg donation (113).
Some of the studies reported decreased numbers of macrophages in the decidua of pre-eclamptic patients (114, 115).
Within the innate immune system, decidual NK cells and antigen presenting cells (including dendritic cells and macrophages) make up a large proportion of the decidual leukocyte population, and are thought to modulate vascular remodeling and trophoblast invasion. At the time, he proposed that three factors contribute to this phenomenon: (1) the anatomical separation between the mother and the fetus, (2) the reduced antigenic property of the fetus, and (3) the immunological inertness of the maternal immune system. Additionally, although direct MHC presentation of fetal antigens by fetal cells generally does not occur, fetal antigens can be processed and presented by maternal antigen presenting cells (APCs) at the fetal–maternal interface (7).
Therefore, exploring the characteristics of the decidual APCs and their interaction with decidual T cells is of great importance in the understanding of fetal–maternal immune tolerance.
However, it is important to note that in contrast to mice, lymphatic vessels are abundant and CCL21 is expressed within the human decidua (20, 21), which therefore might facilitate decidual DC migration in humans. Nevertheless, in monocyte-derived DCs, DC-SIGN is one of the markers upregulated in maturing DCs in mice (33) and humans (39). Interestingly, the authors found these cells to be unique to the decidua in pregnancy and not in normal non-pregnant endometrium.
Interestingly, during early pregnancy, dNK accumulate as a dense infiltrate around the trophoblast cells, but they progressively decrease in number from mid-gestation onward (50). As HLA-C is dimorphic and KIR polymorphic, it has been shown that certain combinations of maternal KIR and fetal HLA-C lead to an increased risk of pre-eclampsia, possibly through modulation of trophoblast migration, implying that HLA-C–KIR interaction is important in placentation (54, 55). Th17 cells, the pro-inflammatory antagonist of Treg cells have also become a focus of studies in the last few years.
Macrophages are abundantly present in the endometrium and play a role in implantation and placentation in normal pregnancy. In pre-eclampsia, there appear to be increased numbers of M1 macrophages, suggesting a role for these macrophages in the poor placental development in pre-eclampsia.
In humans, the monocyte subsets can be distinguished based on the expression of CD14, the lipopolysaccharide (LPS) receptor.
It has been suggested, that to compensate for such changes in the specific immune response, also the innate immune response has to adapt to pregnancy. Whether stimulated cytokine production of pregnant monocytes is increased or decreased as compared to non-pregnant women seems to depend on the stimulus. In our recent study, we observed decreased numbers of classical monocytes and an increased numbers of intermediate monocytes in women with pre-eclampsia as compared with normal pregnant women (41). This notion is supported by the fact that monocytes become activated during their passage through the placenta (5). Direct or indirect contact (via soluble factors) of monocytes with the syncytiotrophoblast may results in monocyte activation. On the other hand, decreased levels of the anti-inflammatory cytokine IL-10 have been observed in the placenta of pre-eclamptic women (66, 67). Differences may amongst others relate to differences in cytokine production between states of monocytes activation, since we have previously shown that activation of monocytes with E coli LPS or P. Although not completely similar, like humans, rats have a hemochorial placenta, showing deep trophoblast invasion into the uterine wall (74) indicating that fetal–maternal interactions may be similar in rat and human pregnancy. Together, these animal studies support the hypothesis that activation of monocytes in pregnancy may result in pre-eclampsia-like signs, such as hypertension and proteinuria.
Via a vicious circle, these cytokines may further activate the monocytes themselves as well as the endothelial cells, finally resulting in the signs of pre-eclampsia, such as proteinuria and hypertension (Figure 2B).
Numbers non-classical monocytes are increased and they may play an important role in this inflammatory process, since they are known to produce increased numbers of cytokines upon activation (4).
The number of decidual macrophages may vary with gestational age being highest in the first and second trimester (88). This suggests that macrophages may be important in the very early phases of spiral artery remodeling, preparing the spiral arteries for further remodeling by trophoblast cells (93).
Next to the typical M2 cytokine gene expression, these decidual macrophages also showed gene expression for inflammatory cytokines such as IL-6 and TNFα (102, 107). This lesion consisted of maternal cells, expressing high levels of CD14 and CD163, suggesting the presence of M2 macrophages. Most of the studies, however, found increased numbers of macrophages in pre-eclamptic patients (112, 116–118).
On the other hand, within the adaptive immune system, Foxp3+ regulatory T cells are crucial for ensuring immune tolerance toward the semi-allogeneic fetus. Indeed, various different subsets of maternal immune cells are present at the fetal–maternal interface, which is the decidua, the mucous membrane (endometrium) of the pregnant uterus. In addition, these macrophages were less able to differentiate into mature DCs in vitro under polarizing conditions, possibly owing to their production of IL-10 (27).
In addition, these cells show a high proliferative rate and good antigen uptake, but poor stimulatory activity in MLR. These APCs may be matured into CD83+ mature DCs (mDCs) under the influence of inflammatory cytokines, which in healthy pregnancy is minimal. This timing seems to implicate that dNK cells may be involved in modulating trophoblast invasion and vascular remodeling.


However, NK cell KIR and HLA-C mismatch clearly does not explain all cases of pre-eclampsia, since only 30% of pre-eclamptic pregnancies have the at-risk maternal KIR phenotype (KIR AA) (54). Some have suggested that this expansion of Treg cell is not allo-antigen driven at least in the mice, as both syngeneically and allogeneically pregnant mice show expansion of the Treg cell population (70).
In pre-eclampsia, these macrophages appear to be present in larger numbers and are also activated. Broadly, they can be classified into two groups: M1 or classically activated macrophages, and M2 or alternatively activated macrophages (18). This has most often been shown by increased numbers of circulating monocytes and granulocytes, resulting in increased number of total leukocytes during pregnancy (28–30). After stimulation with only LPS cytokine production by monocytes from pregnant women was decreased as compared with cytokine production by monocytes from non-pregnant women (30, 36, 37). A role for activated monocytes in parturition can also be deduced from data from pre-term labor, where increased expression of activation markers by monocytes has been observed compared with healthy pregnancy (49).
It is, however, unsure whether this activation of monocytes occurs due to direct contact, since several soluble placental products, such as cytokines (57), placental microparticles (58), fetal DNA (59), released into the maternal circulation, may also activate monocytes (60). The maternal part of the placenta consists of decidua in which remodeled spiral arteries are present, which take maternal blood to the intervillous space. These increased levels of pro-inflammatory cytokines in the pre-eclamptic placenta may be responsible for the increased circulating levels of these cytokines in pre-eclamptic patients (68, 69).
Therefore pregnancy-induced changes in the immune response may also be similar to human pregnancy. Macrophages in the decidua are usually associated with spiral arteries and glands as well as with extravillous trophoblast (86, 89), but are also found in the myometrium (85).
Their suggested role in vascular remodeling is in accordance with the findings of production of factors associated with angiogenesis and tissue remodeling by these cells (94, 95). The production of pro-inflammatory cytokines by decidual macrophages may also be explained by the presence of two macrophage subpopulations in the early decidua (107). In addition, as it has been suggested that non-classical monocytes preferentially differentiate into M2 macrophages (20), it may be speculated that the increased numbers of non-classical monocytes in the circulation during pregnancy (41), results in increased invasion of these cells into the decidua to become M2 macrophages. These data may not necessarily be conflicting, since not only different methods were used (Williams and Burk performed a flow cytometric study, while the other studies were immunohistochemical studies), also different antibodies were used. Nevertheless, at least in mice, decidual CD11c+ DCs appear to be important for the initiation of pregnancy and maintenance of immune tolerance. Notably however, their data showed that dMacs expressed higher level of HLA-DR, as well as the co-stimulatory molecule CD80, compared to peripheral blood monocytes. Thus, it is likely that dMacs are a special subset of APCs specialized in tolerance induction. Importantly, these cells have a veiled appearance typical of immature DCs on immunohistochemistry and can be matured in vitro with a cocktail of inflammatory cytokines into CD83+ mature DCs, with decreased CD14 and DC-SIGN expression, as well as potent stimulatory activity in MLR. The tolerogenic properties are likely induced by IL-10, which is known to upregulate HLA-G and ILT4 (44, 45).
Indeed, dNK have been shown to produce vascular endothelial growth factor C (VEGFC), placental growth factor (PIGF), and angiopoietin 2 (ANG2). However, the authors did not show a direct comparison of Treg cell percentage between syngeneic and allogeneic pregnancies.
In the present review, we focused on the role of monocytes and macrophages in the pathophysiology of pre-eclampsia. These subsets differ in receptor, cytokine, and chemokine expression and in effector function (18).
However, after stimulation of monocytes with both LPS and IFNγ, monocytes of pregnant women showed increased cytokine production as compared with monocytes from non-pregnant women (38). Indeed, similar phenotypical and functional activation of monocytes during the course of pregnancy have been observed in rats as compared with humans (75, 76).
This vicious circle of activation of monocytes and endothelial cells finally results in the symptoms of pre-eclampsia, such as hypertension and proteinuria. When the presence of macrophages in the decidua was first discovered, it was suggested that these cells were recruited as the result of an immune response to the semi-allogeneic fetus (90). Indeed macrophages, which were MMP 9 positive, and which were shown to have phagocytotic capacities were found to infiltrate spiral arteries during remodeling (96). One of these subsets may be a more pro-inflammatory subset, since this subset expressed genes associated with inflammation.
More recently, studies are beginning to unravel the potential interactions between the innate and the adaptive immune system within the decidua, that are required to maintain a healthy pregnancy.
The decidua is therefore, an important site where the maternal immune system encounters fetal antigens and must develop tolerance mechanisms. In addition, there is evidence that dMacs are also involved in vascular remodeling (5, 32) and parturition in the peripartum period (33, 34).
More recently, we examined decidual CD14+ APCs in more detail during healthy pregnancy and pre-eclampsia using multi-color flow cytometry (38).
The second subset of monocytes is characterized by low expression of CD14 together with CD16. M1 macrophages are microbicidal and inflammatory, M2 macrophages are immunomodulatory, which can induce tolerance and the resolution of inflammation, and are only weak microbicidal (18). Although these findings seem contradictory, they can be explained as follows: decreased cytokine production of monocytes from pregnant women following LPS stimulation is a sign of activation of monocytes, since activated monocytes become tolerant to LPS (39).
The reason for this difference is unclear, but may be due to differences in experimental methods.
As explained above, this may be due to different techniques used, but may also be due to a different selection of patient groups (we exclusively included early onset pre-eclamptic women, while Al-ofi et al.
Since monocytes themselves are potent producers of cytokines, the activation of monocyte by placental factors and cytokines may in turn result in a vicious circle of monocytes activation and cytokine production leading to persistent increased monocyte activation in pre-eclampsia. Moreover, in accordance with human pregnancy, we found decreased numbers of classical monocytes and increased numbers of non-classical monocytes during pregnancy in this species (41).
However, it is now generally accepted that macrophages, and other immune cells present in the decidua, are necessary for successful implantation (85). Macrophages have also been shown to be important for clearance of apoptotic cells in the decidua (97). The other subset, which was higher in number, expressed genes associated with extracellular matrix formation, networking, communication, and growth (107).
In this review, we discuss the recent advances exploring the complex crosstalk between the innate and the adaptive immune system during human pregnancy.
They also showed that dDCs were more likely to prime CD4 cells into a Th2 phenotype compared to their peripheral counterparts (17). Indeed, dNK cells are thought to be the mediator of fetal demise in IL-10-deficient mice treated with LPS, which conversely can be rescued by administration of IL-10 (57).
It has been suggested that these two populations may be extreme ends of polarization and that macrophages may actively switch their phenotype, depending on the environment (19). Further studies are warranted to evaluate whether the subsets respond differently to stimulation in pregnant and non-pregnant women. Various studies have focused on specific functions of macrophages in the decidua and it has been suggested that the decidual macrophages have various roles during pregnancy, mainly in placentation (91), but they may also play a role in protecting the fetus against intrauterine infection (92). Apoptosis is an important process during spiral artery remodeling and trophoblast invasion. The authors concluded that such polarization of the immune response toward Th2 has potential roles in averting Th1-mediated rejection of the fetus.
They further showed that expression of these markers were higher earlier in the gestation, implying greater dMac activation at the time of implantation. Since then, other studies have demonstrated the fetal antigen-specific nature of maternal Treg cells during pregnancy (72, 73), further supporting the role of fetal allo-antigen in Treg cell expansion. More recently, a third, intermediate subset of monocytes has been defined, called the intermediate subset (13). Therefore, if LPS tolerance is abrogated by IFNγ during pregnancy, monocytes produce increased amounts of cytokines during pregnancy. During these processes, apoptotic trophoblast cells (98) as well apoptotic cells in the vascular wall that is being remodeled have been observed (93).
This subset is characterized by high expression of CD14 in combination with expression of CD16 and is a separate subset of monocytes. The above mentioned studies have been performed in the third trimester of pregnancy and based on all above mentioned data, it is now generally accepted that monocytes are activated during pregnancy.
By engulfment of the apoptotic cells, macrophages prevent the release of pro-inflammatory substances from the apoptotic cells into the decidua [reviewed in Ref. The authors found that compared to peripheral blood macrophages, dMacs have a gene expression profile, which biases toward alternatively activated macrophages or M2 phenotype, which suggests that dMacs are likely immunosuppressive (29). It has been suggested that classical monocytes arise from the bone marrow and mature into non-classical monocytes via intermediate monocytes (13, 14). These subsets differ in many respects, including expression of adhesion molecules and chemokine receptors and function [reviewed in Ref. However, gradually developing monocyte activation may occur during the course of pregnancy, since one paper showed progressive phenotypical activation of monocytes from the first trimester to the third trimester (34). Using gene expression profiles, the authors here showed that neither of the CD11chi or CD11clo macrophages corresponds to in vitro differentiated M1 or M2 macrophages exactly, though CD11chi macrophages were skewed toward maternal peripheral blood monocytes and shared common genes with synovial macrophages from rheumatoid arthritis patients. Classical monocytes are professional phagocytes that can generate reactive oxygen species (ROS) and produce cytokines in response to toll-like receptor dependent activation by f.i. In the same study, the authors showed that CD11chi dMac produced significantly more TNFα, IL-6, and paradoxically IL-10 compared to CD11clo macrophages.
On the other hand, there was a slight trend toward increased TGFβ secretion by CD11clo cells. Non-classical monocytes are weak phagocytes and do not generate ROS, but are more efficient producers of pro-inflammatory cytokines after TLR dependent activation (12).
This subset has been shown to have a longer half-life and localize to both resting and inflamed tissue (12).
They crawl on the luminal side of the endothelium and survey endothelial cells and tissues for damage and infection (13). Upon damage or infection, they may rapidly invade the tissue and initiate the inflammatory response (15).
Non-classical monocytes have been shown to be increased in various inflammatory diseases (13, 16, 17).



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