Hum. Reprod. Advance Access originally published online on July 30, 2007
Human Reproduction 2007 22(10):2577-2584; doi:10.1093/humrep/dem246
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OPINION |
Tubal ectopic pregnancy: macrophages under the microscope
1 Laboratorio di Analisi, Ospedale Mater Salutis, via C. Gianella, 1-37045 Legnago, Verona, Italy 2 Istituto di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Ospedale Policlinico G.B. Rossi, Verona, Italy
3 Correspondence address. Tel: +39-442-632264; Fax: +39-442-632323; E-mail: a_tonello{at}yahoo.it
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Abstract |
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 Top Abstract IntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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BACKGROUND: Ectopic pregnancy (EP) is a major reproductive health issue, whose underlying causes remain largely unknown. The unusual macrophage presence in the oviduct affected by EP could indicate macrophage contribution to the pathology.
METHODS: Macrophages have important functions in reproduction that are reviewed in this work. They are needed for tissue remodelling and immune-regulatory roles, and are present both in the ovary and uterus. Numerous cytokines regulate monocytes recruitment, differentiation and function in the reproductive tract, among them leukaemia inhibitory factor (LIF), colony-stimulating factor 1 and transforming growth factor-
are indispensable and non-redundant for reproductive outcome. Cytokine types and levels are modulated by estrogen, progesterone and seminal plasma, which drive the differentiation of monocytes to immunity cells or to immunosuppressed trophic and scavenging macrophages.
RESULTS: Many risk factors for EP involve an inflammatory reaction that can induce the release of mononuclear phagocytes from the bone marrow and/or favour immunosuppressed trophic differentiation of newly recruited mononuclear phagocytes in the reproductive tract. These observations strengthen the hypothesis that immunosuppressed trophic and scavenging macrophages may have a role in EP onset.
CONCLUSIONS: Macrophages may contribute to the regulation of tubal motility through prostaglandin production and induction of progesterone secretion. Considerations about LIF also suggest that macrophages may have a central role in ectopic receptivity.
Key words: ectopic pregnancy/estrogen/Fallopian tube/macrophage/progesterone
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Introduction |
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TopAbstractIntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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Ectopic pregnancy (EP) is a life and fertility threatening event, which occurs in 1.3–2% of all reported pregnancies in the western world (Farquhar, 2005
). There is practically no evidence of tubal EP in organisms other than humans (Corpa, 2006), and functional studies on underlying causes are few and far between. Analysis of risk factors has been done to identify causes of impaired oviductal transport and consequent embryo retention in the Fallopian tube, and it has been demonstrated that smoke components decrease both ciliary beat frequency and oocyte–cumulus complex pick-up rate of hamster oviducts in vitro (Talbot et al., 1998). However, retention in the oviduct does not result in EP in mice, even if trapped blastocysts are morphologically normal and they implant upon transfer into pseudopregnant recipient uteri (Wang et al., 2004). These observations suggest that there should be other concomitant alterations in the human oviduct to permit implantation, alterations that are not present in the studied animal models.
Looking for possible alterations predisposing to EP, we compared the ectopic tube to the normal tube and to the endometrial stroma. The stroma compartment of the human endometrium has been extensively studied, both during the menstrual cycle and in pregnancy. Besides fibroblasts, leukocytes represent an important fraction of decidual cells. In the first trimester of pregnancy, 30% of cells in the decidual stroma are leukocytes, of which 20–30% are macrophages (Bulmer, 1995). The major contributors to the leukocyte infiltrate are the CD56 + NK cells, which account for up to 70% of the leukocyte population in the first trimester decidua (Bulmer, 1995). In EP, the distribution patterns of macrophages, T cells and B cells found in tubal implantation sites are similar to those found in normal intrauterine implantation sites (von Rango et al., 2001). In EP, macrophages and T lymphocytes form the predominant leukocyte subpopulation both in the tubal implantation site and in the tubal mucosa away from the implantation site (Vassiliadou and Bulmer, 1998a,b), but CD56 + cells are never present in the tubal mucosa, although they are always present in conspicuous fractions in intrauterine decidual tissue (Vassiliadou and Bulmer, 1998a,b; von Rango et al., 2001). Significantly fewer leukocytes are found within the tubal mucosa during the normal menstrual cycle than in the tubal wall distant from the implantation site in tubal EP. The macrophage density is more than doubled in EP and it is mainly responsible for the difference in the number of leukocytes (von Rango et al., 2001). Is this finding the sign of an involvement of macrophages in EP development? To test this hypothesis, we reviewed the literature regarding these cells in reproduction. We paid special attention to the effects exerted on macrophages by cytokines such as leukaemia inhibitory factor (LIF), colony-stimulating factor 1 (CSF-1) and transforming growth factor (TGF-), which are essential and non-redundant for reproductive outcome, as highlighted by targeted gene disruption (Makrigiannakis et al., 2006). Interleukin (IL)-11, the other cytokine identified as indispensable for reproduction, can also modulate macrophage activation (Schwertschlag et al., 1999) and is expressed in EP (von Rango et al., 2004) but, to date, knowledge on its functions in implantation is only at a preliminary level, so we will make no more mention of it.
Macrophages carry out tissue remodelling functions and immune-regulatory roles in the reproductive tract. EP risk factors can alter their recruitment and/or differentiation programmes and evidence will be presented that macrophages are appealing candidates for at least a partial and perhaps prominent causal role in the development of EP.
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Macrophage roles in reproduction |
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TopAbstractIntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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Macrophages are important accessory cells for reproductive functions and are found abundantly in the reproductive tract of both males and females (Cohen et al., 1999
). In the ovary and testis, macrophages are in close proximity to steroidogenic cells. They are present in the ovarian interstitial tissue but are excluded from the germ cell compartment, except in atretic follicles, where macrophage migration might contribute to the destruction of the defunct follicle. During oocyte development in mice, rats and humans, macrophages are recruited into the theca layers of the follicle so they are most numerous just before ovulation (Cohen et al., 1997). Macrophages are also preferentially localized to the cortical surface of pre-ovulatory follicles, where they may assist in the process of follicle rupture and potentially in the post-ovulatory tissue remodelling, associated with conversion of the ruptured follicle to a corpus luteum (Brannstrom et al., 1994; Brannstrom and Enskog, 2002). Macrophages contribute to the regulation of steroidogenesis, as demonstrated by experiments showing increased progesterone secretion by granulosa and luteal cells following co-culture with macrophages (Halme et al., 1985).
In the adult uterine stroma, macrophages undergo dramatic fluctuations in response to the changing hormonal milieu (Hunt and Robertson, 1996; Cohen et al., 1999). In mice, their density is lowest at diestrus during periods of relative estrogen depletion and increases to 
20% of the stromal cells at proestrus, under the influence of estrogen (Hunt and Robertson, 1996; De and Wood, 1990). Cyclic changes in the number of endometrial macrophages are also a feature of the human menstrual cycle. Macrophages increase by 45% between the proliferative and early secretory stages (Bulmer, 1995). Unlike the situation in rodents, where macrophage density declines as the cycle reaches completion, the number of these cells continues to increase in the late secretory stages of the menstrual cycle. These differences may relate to the absence (rodent) or presence (women) of endometrial shedding and repair, processes where macrophages would be useful (Hunt and Robertson, 1996).
Epithelial cells in mouse uteri respond to signals from ovarian steroid hormones by producing an array of cytokines that are known to regulate macrophage recruitment, survival, differentiation and/or function (Robertson et al., 1994). These include CSF-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-
(TNF-) and IL-6. In mouse uterine epithelial cells, synthesis of CSF-1 is stimulated by estrogen and progesterone, whereas GM-CSF is stimulated by estrogen and moderately inhibited by progesterone (Robertson et al., 1996). Following mating, the macrophage uterine population is sustained (Robertson et al., 1997), and during pregnancy, it increases in density compared with other types of uterine cells. This has been demonstrated in mouse, rat and human uteri (Bulmer, 1995; Hunt and Robertson, 1996).
LIF, a member of the IL-6 family, is a highly glycosylated 40–50 kDa glycoprotein with a broad range of biological functions (Haines et al., 2000). LIF signalling in the endometrium is essential for embryo implantation, whereas embryos lacking components of the LIF receptor complex will implant normally (Stewart et al., 1992; Song et al., 2000). LIF exerts at least some of its functions by means of macrophages. Comparison of LIF knockout and wild-type mice suggests that LIF has a greater effect on leukocyte dynamics and distribution. The percentage of macrophages is reduced by more than half in the LIF knockout mice on day 3 of pregnancy, and their distribution is disrupted, suggesting that LIF is a chemokine for these cells (Schofield and Kimber, 2005). LIF has been shown to be a chemoattractant for macrophages in other tissues, such as in the nervous system, where it works in conjunction with other chemokines, such as IL-6 and oncostatin M, to recruit macrophages (Tofaris et al., 2002). LIF can also induce macrophage maturation (Hilton et al., 1988; Laabi et al., 2000).
CSF-1 functions in reproduction
The CSF-1-null mutant mouse has severely depleted macrophage populations in many tissues (Pollard and Stanley, 1996). It is interesting that the study of macrophage populations suggests that the tissue density of those macrophages that have scavenging/trophic roles is dramatically affected by the absence of CSF-1, whereas those that populate immune organs are relatively less affected (Pollard and Stanley, 1996). Analysis of mice that are deficient for macrophages and other mononuclear phagocytic cells (such as osteoclasts) because of a null mutation in CSF-1 shows that these cells have a significant role in the morphogenesis of many tissues (Pollard and Stanley, 1996; Pollard, 1997). Developmental defects include osteopetrosis, dermal hypoplasia, aberrant development of the sex-steroid-hormone feedback response in the brain, delayed and aberrant pancreatic morphogenesis and impaired branched morphogenesis of the mammary gland.
In the CSF-1 deficient mouse, low-pregnancy rates and smaller litter sizes are observed compared with the wild-type mouse (Pollard et al., 1991). The major effects of CSF-1 deficiency on the female reproductive function are disrupted estrous cycle and lower-ovulation rate (Cohen et al., 1997). The receptor for CSF-1, the product of the c-fms proto-oncogene (Sherr et al., 1985), is a transmembrane tyrosine kinase and is detected in oocytes, preimplantation embryos, ovarian and uterine macrophages, decidual cells and trophoblasts (Cohen et al., 1997). In mice and humans, CSF-1 mRNA can be detected in granulosa cells as the follicle matures and at least in humans, the CSF-1 concentration of follicular fluid is significantly higher than the serum (Witt and Pollard, 1997). Since CSF-1 is a chemoattractant for macrophages (Webb et al., 1996), it seems probable that the follicle-synthesized CSF-1 plays at least a part in the recruitment of macrophages proximate to the developing follicle. As the corpus luteum matures after copulation, the number of macrophages in CSF-1 deficient mice increases until it reaches 35% of the wild-type number (Cohen et al., 1997). This strongly suggests the presence of another macrophage chemoattractant synthesized by the luteal cells.
CSF-1 is produced by the uterine epithelium in response to female sex steroid hormones (Pollard et al., 1987) and studies with CSF-1 deficient mice have shown that CSF-1 is a key regulator of the uterine stromal macrophage population, because their numbers are very substantially reduced in such mice (Pollard et al., 1998). In humans, there is increased local production of CSF-1 in tissues found at the maternal-fetal interface during the time of implantation (Kauma et al., 1991) and CSF-1 production continues in the uterine epithelium during pregnancy (Pollard et al., 1987; Arceci et al., 1989; Daiter et al., 1992). Moreover, decidual T cell clones from women suffering from unexplained recurrent abortion display decreased production of CSF-1, as well as of other cytokines, including LIF (Piccinni et al., 2001).
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Seminal plasma and maternal immunotolerance |
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TopAbstractIntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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Artificial insemination in livestock species, which often involves extensive dilution of seminal plasma (SP), results in fertility and fecundity rates which are generally lower than those of natural matings (O'Leary et al., 2006
). Research in rodent species (Robertson and Sharkey, 2001) and pigs (O'Leary et al., 2004) highlights the role of SP in activating the expression of embryotrophic cytokines and preparing the maternal tract for the developing embryo, particularly by facilitating the immune changes required to accommodate pregnancy. In pigs, SP initiates an inflammatory response characterized by the recruitment and activation of endometrial leukocytes. Leukocyte recruitment is elicited after seminal factors signal uterine epithelial cells to induce expression of a number of pro-inflammatory factors, including GM-CSF, IL-6, MCP-1 and a key regulator of prostaglandin synthesis, COX-2 (O'Leary et al., 2004). The effects of SP extend to affect ovarian function: SP exposure is associated with increased ovarian leukocyte recruitment in mice (Gangnuss et al., 2004) and pigs (O'Leary et al., 2006), with macrophages comprising the most abundant cell lineage. SP also induces an increase in plasma progesterone content and makes granulosa cells and thecal tissue from pre-ovulatory follicles more responsive in vitro to growth factor- and gonadotrophin-stimulated cell proliferation (O'Leary et al., 2006). In humans, it is clear that exposure to semen induces neutrophil recruitment into the superficial epithelial layers of the cervix (Pandya and Cohen, 1985) and increases the abundance of macrophages, dendritic cells and lymphocytes in the deeper epithelium and stromal tissues (Robertson et al., 2001).
The post-mating inflammatory response in pigs is transient and by the time the embryo implants it has dissipated, but altered expression patterns of SP induced factors persist during the pre-implantation period (O'Leary et al., 2004). The active component in SP has been identified as TGF- (Tremellen et al., 1998), a cytokine present in abundance in the SP of all mammalian species so far examined (Robertson et al., 2002). Besides tissue remodelling functions, immune-regulatory roles for inflammatory leukocytes have been proposed. Activation of T lymphocytes in draining lymph nodes after mating is consistent with an immune response to antigens in semen (Johansson et al., 2004), potentially facilitating maternal immunotolerance to the conceptus at implantation (Robertson and Sharkey, 2001). The high TGF- content confers potent immunosuppressive activity to SP (Robertson et al., 2002). TGF- suppresses dendritic cell (DC) maturation and function, and favours the differentiation of regulatory T cells, characterized by high expression of TGF- and IL-10 as well. Regulatory T cells can functionally suppress an immune response by influencing the activity of another cell type; they are key mediators of peripheral and mucosal T-cell tolerance (Weiner, 2001; Shevach, 2004). In human semen, there is also an abundance of prostaglandin E2 (PGE2), which is undetectable in rodent and porcine SP (Denison et al., 1999a,b; Robertson et al., 2002). PGE2 contributes to the suppression of DC differentiation and function through its capacity to inhibit IL-12 synthesis (Kalinski et al., 1999; Sombroek et al., 2002). The immune deviating effects of seminal cytokines in the female tract can be amplified by locally synthesized TGF- and PGE2, as well as additional deviating cytokines IL-4, IL-6 and IL-10, secreted from endocervical and endometrial cells in women (Fichorova and Anderson, 1999) and in rodents (Tamada et al., 1990). In the case of IL-10 and IL-6, expression is inducible by seminal factors (Robertson et al., 1992; Denison et al., 1999a,b).
In mice, the inflammatory response elicited by SP terminates in association with rising progesterone levels (Robertson et al., 1996). Progesterone, the dominant hormone of mammalian pregnancy, profoundly influences immune cells and directs them into a generally suppressive profile (Pepe and Albrecht, 1995). For example, progesterone enhances PGE2 production by human placental macrophages (Yagel et al., 1987). PGE2 acts as an autocrine inhibitor for macrophages, in which it suppresses TNF- production (Kunkel et al., 1988).
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Trophic differentiation of macrophages |
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TopAbstractIntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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The macrophage population may be subdivided in two main groups according to different functions and regulation (Pollard and Stanley, 1996
). Trophic and scavenging macrophages are involved in morphogenesis and tissue regeneration, e.g. promoting fibroblast activation and expansion in wound healing. Macrophages with immunological functions are involved in host defence from infections and have no evident effect on fibroblasts. The local cytokine milieu in the reproductive tract determines the differentiation and functions of newly recruited mononuclear phagocytes. The situation is analogous to that of tumour activated macrophages in cancer development (Pollard, 2004; Zou, 2005). As in tumours, CSF-1, produced by granulosa cells and uterine epithelium in the reproductive tract, locally blocks the maturation of dendritic cells, so that they are unable to present antigens, and promotes the development of immunosuppressed trophic macrophages. In support of this hypothesis, studies have shown that renal-carcinoma cell-line production of IL-6 and CSF-1 inhibits DC maturation (Menetrier-Caux et al., 1998). TGF-, IL-10, PGE2 and vascular endothelial growth factor (VEGF) are all immunosuppressive factors with important functions in reproduction. The cytokines that direct macrophages towards more cytotoxic and antigen-presenting phenotypes are GM-CSF, interferon-
(IFN-), IL-4 and IL-12 (Dranoff, 2004; Zou, 2005). The ratio CSF-1:GM-CSF is pivotal in regulating the transition between immunosuppressive and immunostimulatory phenotypes (Dranoff, 2004). In the reproductive tract, the equilibrium between estrogen and progesterone levels should contribute to the balance between these two cytokines, since in the mouse estrogen stimulates synthesis of both CSF-1 and GM-CSF in uterine epithelial cells, whereas progesterone stimulates CSF-1 but inhibits GM-CSF production (Robertson et al., 1996) (Fig. 1). Moreover, studies in GM-CSF null mice have shown that besides the activation of immune functions in macrophages and dendritic cells, GM-CSF is involved in progesterone secretion from the corpus luteum, which is reduced in its maximal level in the absence of GM-CSF (Jasper et al., 2000). Although progesterone secretion during an estrous cycle may occur in the absence of GM-CSF, the increased demand in the case of pregnancy may not be able to be met unless the corpus luteum is fully functional (Jasper et al., 2000). As GM-CSF production in uterine epithelium is stimulated also by SP (O'Leary et al., 2004), the effect of GM-CSF on the maximal level of progesterone synthesis could be a mechanism for modulating immunosuppressive stimuli on the previous inflammatory stimuli elicited by mating, to ensure optimal conditions for embryo implantation.
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Macrophage involvement in EP |
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TopAbstractIntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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In 35–50% of the patients, the main predisposing condition for EP is pelvic inflammatory disease (PID) with salpingitis (Ankum et al., 1996
). The risk of developing an EP augments with successive infections and the onset of chronic inflammation (Hillis et al., 1997). The pathogens most commonly associated with salpingitis are Neisseria gonorrhoeae and Chlamydia trachomatis. Infection with C. trachomatis is particularly serious because Fallopian tube damage and tubal factor infertility are common sequelae. The 60 kDa chlamydial heat shock protein (hsp60) is capable of provoking both a humoral and a cell-mediated immune response, with intense macrophage activation (LaVerda et al., 1999). The exacerbated immune response is believed to result in permanent tissue scarring. Whatever the infecting micro-organism may be, chronic inflammation is always characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes and plasma cells), tissue destruction and attempts at healing, which include angiogenesis and fibrosis. Chronic inflammation usually leads to a diffuse and persistent distribution of macrophages throughout the oviduct, as observed with EP. These observations strengthen the hypothesis of a causal role of macrophages in the onset of EP.
Tubal surgery, sterilization and previous EP are high risk factors (Farquhar, 2005): they cause tissue damage and elicit an inflammatory response that attracts macrophages for wound healing. Besides inflammatory stimuli, which induce release of mononuclear phagocytes from bone marrow and tubal recruitment of macrophages, disturbances to the fine-tuning between immunity and immunotolerance may also play a role in EP development. Many risk factors for EP can favour an unbalanced production of CSF-1 over GM-CSF, thus driving trophic differentiation of newly recruited mononuclear phagocytes (Fig. 1). There is a higher incidence of EP after contraceptive failure in women who had taken progestin-only oral contraceptives or had progestin-only implants compared with pregnant women in the general population (Furlong, 2002), suggesting a role for the immunosuppressive activity of progesterone in EP onset. Having more than one sexual partner, another recognized risk factor for EP (Farquhar, 2005), provokes multiple inflammatory stimuli, in order to achieve immunotolerance to all the possible paternal antigens, so it may increase macrophage recruitment compared with monogamy and also enhance the maximal level of progesterone synthesis. Infections favour macrophage recruitment, but stimulate the production of factors, such as TNF, GM-CSF and IFN, that direct macrophages towards cytotoxic and antigen-presenting phenotypes. This could be the reason why tubal infections are associated with a lower risk of EP compared with tubal surgery (Ankum et al., 1996) and smoking (Hillis et al., 1997), which elicit macrophage activation without immunogenic stimuli and direct them towards trophic functions. If we consider smoking as a risk factor, we can suppose that every inflammatory event that induces the release of mononuclear phagocytes from bone marrow may contribute to the recruitment of macrophages in the reproductive tract, even if its location is far away from the müllerian system. Indeed, the localization process of inflammatory cells is not particularly efficient and many of the cells released from the marrow in the circulation actually become distributed to other locations of no obvious relevance to the inflammatory response (Metcalf et al., 1996).
All the above mentioned risk factors can be associated with stimulation of macrophage production and/or trophic differentiation, and this reinforces macrophage involvement in EP onset and suggests that macrophages may have undervalued functions in the control of tubal motility and/or in the process of blastocyst implantation.
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Discussion |
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TopAbstractIntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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The development of an EP has never been observed, owing to the lack of animal models, and studies on EP only investigate the pathology after the implantation has occurred. Numerous studies show that there are no differences in the abundance of macrophages between uterine and tubal implantation sites (Vassiliadou and Bulmer, 1998a
,b; von Rango et al., 2001). The similar numbers of macrophages in both situations could on the surface appear to argue against a role for these cells in initiating EP. The increase in macrophages at the implantation site in EP could be in response to the pregnancy and not a cause of it. However in EP, the macrophage density is more than doubled also in the tubal wall distant from the implantation site, where the effects of pregnancy should be reduced. This finding argues for a higher macrophage presence in the ectopic tube before blastocyst implantation, which means that the involvement of macrophages at the beginning of the pathology cannot be excluded.
Analysis of risk factors emerging from epidemiological studies gives an important sign of macrophage involvement in EP. Genital tract infections with chronic salpingitis result in the diffuse and persistent distribution of macrophages throughout the Fallopian tube. High risk factors, which include tubal surgery, sterilization and previous EP (Farquhar, 2005), cause tissue damage that elicits an inflammatory response and attracts macrophages to get wound healing. Mononuclear phagocytes migrate from the venous system to the site of tissue injury, guided to the site by chemotactic factors. Once present, they differentiate into mature trophic and scavenging macrophages or immature dendritic cells (Osusky et al., 1997). Activated macrophages are the main source of growth factors and cytokines [TGF-, VEGF, platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), TNF-, IL-1, etc.] that modulate tissue repair (Coussens and Werb, 2002). Many of these factors have important roles in uterine decidualization as well (Dey et al., 2004). Another recognized risk factor for EP is smoking, which provokes exposition to chemical irritants that elicit non-immunogenic inflammatory stimuli, and drive immunosuppressed trophic differentiation of macrophages, as also happens in pulmonary alveoli, so as to prevent aberrant immune responses to harmless environmental agents (Bilyk and Holt, 1993; Strickland et al., 1996). It is demonstrated that smoke effects extend to the entire organism. Smoke action on macrophages may explain the surprising observation that pelvic infections contribute less to EP risk than does smoking.
What role might macrophages have in EP onset? An EP develops when blastocyst is trapped in the Fallopian tube and implants. Therefore, an altered tubal motility and a tubal propensity to receptivity are two necessary conditions for EP onset. Macrophages could take part in both processes. As to tubal motility, it is influenced by progesterone, estrogen and prostaglandins (Arbab et al., 2002), with progesterone and prostaglandins causing smooth muscle relaxation (Roblero and Garavagno, 1979; Arbab et al., 2002) and high levels of progesterone causing ciliary dysfunction (Paltieli et al., 2000). Activated macrophages increase progesterone secretion by granulosa and luteal cells (Halme et al., 1985) and in turn progesterone enhances PGE2 production by macrophages (Yagel et al., 1987). Thereafter, we can surmise that, in presence of an elevated number of macrophages, the concentration of progesterone and prostaglandins would be enough to impair tubal motility and cause embryo retention in the oviduct.
Considerations about LIF give some suggestions about tubal receptivity. In the process of uterine implantation, maternal LIF is essential. The percentage of macrophages is reduced by more than half in LIF-null mice on day 3 of pregnancy and their distribution is also altered, suggesting that LIF is a chemokine for these cells (Schofield and Kimber, 2005). However, by day 4, macrophage density appears similar to that in the wild-type mice. CD56 + NK cells are detected as early as day 3 of pregnancy in wild-type and LIF-null mice, but the LIF knockout uteri have double the wild-type percentage of NK cells at day 3. So it is possible that LIF restricts migration of NK cells into the uterus. Keltz et al. (1996) observed that LIF is expressed in the human oviduct without significant variation during the menstrual cycle. Epithelial cells secrete higher levels of LIF compared with stromal cells. Yet the treatment of tubal stromal cells with the inflammatory cytokines IL-1 and TNF- and with the growth factors TGF-, endothelial growth factor (EGF) and PDGF induces a striking enhancement of LIF expression and secretion. Hence a tubal inflammatory process may increase LIF production by oviducts and LIF may contribute to the recruitment of trophic macrophages. The presence of trophic macrophages and the absence of NK cells could predispose to the onset of EP. Macrophages could be necessary for the tissue remodelling needed for the blastocyst to infiltrate the stroma. Then the absence of CD56 + uterine NK cells could permit trophoblast cells to invade deeply into the tubal wall. It is interesting to note that LIF mRNA levels are higher in the isthmic segment of the Fallopian tube when associated with an EP compared with that in normal tubes from non-pregnant subjects (Keltz et al., 1996). Moreover, there is a higher level of LIF in perimenopausal tubes in women between ages 47 and 53 years (Keltz et al., 1996). This enhanced production of LIF could augment macrophage recruitment in the oviduct and contribute to the higher incidence of EP with aging.
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Conclusion |
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TopAbstractIntroductionMacrophage roles in reproductionSeminal plasma and maternal...Trophic differentiation of...Macrophage involvement in EPDiscussionConclusionReferences |
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Current knowledge on reproduction cannot explain the cellular and molecular mechanisms causing blastocyst ectopic implantation and animal models are missing. Our attention was attracted from macrophages that are present in the ectopic tube and have important tissue remodelling and immune-regulatory roles in reproduction. Evidences are presented that proper recruitment and differentiation of macrophages might be crucial for the reproductive outcome. Factors that perturb macrophage recruitment and differentiation might affect fertility and have effects both on tubal motility and propensity to receptivity. These observations may be significant not only for EP but also for normal uterine pregnancy as well. For example, the effect of high estrogen levels on macrophage differentiation may explain the poor pregnancy success rate in assisted reproduction (about 30%), due to the transfer of IVF-derived embryos into non-receptive uteri (Dey et al., 2004
). In fact, estrogen stimulates the production of GM-CSF, which favours immunity cell maturation to the detriment of trophic macrophages, this is possibly the original defect in receptivity. Overall, the data reviewed in this work suggest that macrophage involvement may be a good starting point for understanding how and why EP arises.
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Submitted on March 28, 2007; resubmitted on May 25, 2007; accepted on June 29, 2007.
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