|Year : 2019 | Volume
| Issue : 3 | Page : 177-184
Cyclooxygenase-2 and decidual immune cells
Si-Yao Ha1, Hui-Li Yang1, Zhen-Zhen Lai1, Lu-Yu Ruan1, Jia-Wei Shi1, Ming-Qing Li2
1 Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
2 Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080; Laboratory for Reproductive Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011; Laboratory for Reproductive Immunology, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai 230032, China
|Date of Submission||11-Apr-2019|
|Date of Web Publication||27-Sep-2019|
Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, No. 1326, Pingliang Road, Shanghai 200080
Source of Support: None, Conflict of Interest: None
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in arachidonic acid (AA) metabolism. COX-2 and its products (prostanoids) serve versatile biological functions during pregnancy. Numerous evidences demonstrate special reprogramming of COX-2-catalyzing AA metabolism in decidual immune cells (DICs), particularly in decidual macrophages, corresponding to special gestational phases. This review summarizes the reprogramming of COX-2-catalyzing AA metabolism in DICs as well as the immunoregulation of diverse COX-2-generating prostanoids in DICs during the different phases of gestation.
Keywords: Cyclooxygenase-2; Decidual Immune Cell; Metabolism; Pregnancy; Prostanoid
|How to cite this article:|
Ha SY, Yang HL, Lai ZZ, Ruan LY, Shi JW, Li MQ. Cyclooxygenase-2 and decidual immune cells. Reprod Dev Med 2019;3:177-84
| Introduction|| |
The emerging field of immunometabolism has substantially progressed in recent years and provided novel insights into distinct metabolic regulators and reprogramming pathways of immune cell populations under various immunological settings.,,, Nevertheless, studies regarding immunometabolic reprogramming in the field of reproduction–immunity are still sparse. A genetically distinct fetus poses an immunological challenge to a pregnant female. During gestation, intricate crosstalk occur at the maternal–fetal interface, such as the formation of a functional synapse between invading fetal extravillous trophoblast cells and the involvement of various maternal immune cell subsets, epigenetically modified decidual stromal cells (DSCs), and decidual mesenchymal stem cells (dMSCs) synergistically creating a tolerogenic niche to support semiallogeneic fetal development., Among these factors, decidual immune cells (DICs), mainly consisting of T cells (10%–20%), decidual natural killer cells (dNKs, 50%–70%), decidual macrophages (dMφs, approximately 20%), and decidual dendritic cells (dDCs), adapt their phenotypic and functional characteristics in response to the special tissue microenvironment in order to provide an immunoprivileged matrix essential for embryo implantation, remodeling of the maternal spiral arteries, placental development, and labor.,,,,,,
Cyclooxygenases (COXs), officially known as prostaglandin–endoperoxide synthase (PTGS), are rate-limiting enzymes responsible for prostanoid formation during arachidonic acid (AA) metabolism. In the past 30 years, several studies have highlighted the role of COX-2, a type of COX, in multiple pregnancy processes including ovulation,,, fertilization,,, implantation,,,,, and parturition.,,, Given that DICs have been implicated in these processes, this review summarizes the reprogramming of COX-2-catalyzing AA metabolism in DICs as well as the immunoregulation of diverse COX-2-generating prostanoids in DICs during the different phases of gestation.
| Cyclooxygenase-2|| |
There are three isozymes of COXs encoded by distinct genes: a constitutive COX-1, an inducible COX-2, and a splice variant of COX-1 termed COX-3, all of which differ in their regulation of expression and tissue distribution. COX-1 encoded by the “housekeeping” gene, PTGS-1, is a constitutive enzyme associated with the endoplasmic reticulum (ER), which regulates angiogenesis in endothelial cells, maintains tissue homeostasis, and promotes cell proliferation during tumor progression., COX-3 is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron that is not retained in COX-1; however, it does not result in a functional protein in humans.
Monotopic membrane protein COX-2, which was discovered in the laboratory of Daniel Simmons in the 1990s, is encoded by the “rapid response” gene, PTGS-2, and isassociated with both the nuclear envelope and ER. COX-2 shares ~60% amino acid sequence identity and structural homology (rmsd <1.0 Š) with COX-1. As a homodimer, it contains two separate active sites: (1) a COX active site that catalyzes the oxygenation of polyunsaturated fatty acids to hydroperoxy endoperoxides and (2) a peroxidase active site that reduces the hydroperoxide to alcohol. COX-2 is primarily an inducible enzyme (constitutively expressed in key regions of the body such as the brain, lungs, thymus, gut, and kidneys) whose expression is activated in a variety of cells in response to cytokines, mitogens, and endotoxins., A direct feedback is also observed between COX-2 and its products. COX-2 is a rate-limiting enzyme that converts AA to prostaglandin endoperoxide H2 (PGH2). PGH2, an unstable reaction intermediate, is subsequently converted into either prostaglandins (PGs, such as PGD2, PGE2, PGF2a, and PGI2) or thromboxane A2 (TXA2) by the action of specific synthases., They are ubiquitously produced, usually each cell type generates one or two dominant products, and act as autocrine and paracrine lipid mediators to maintain local homeostasis in the body. Each prostanoid acts preferentially with its corresponding receptors, i.e., PGD2 receptors (DP and CRTH2), PGE2 receptors (EP1, EP2, EP3, and EP4), PGF2a receptor (FP), PGI2 receptor (IP), and TXA2 receptor (TP),, to activate inhibitory or stimulatory transmembrane G protein-coupled EP or the nuclear receptor, PPARβ.,, COX-2 has long been known to be a target for pain relief, inflammation treatment,,,,,, and the modulation of multiple procarcinogenic effects.,,,,
The 1990s was the first time when the targeted disruption of COX-2 in mice was demonstrated to result in multiple failures in female reproductive processes. Consequently, the role of COX-2 in ovulation,,, fertilization,,, implantation,,,,, and parturition ,,, has been studied extensively. In the reproductive system, COX-1, constitutively expressed in the decidual lining of the uterus, is involved in the homeostasis and survival of the fetus without modulation during gestation or labor,,, whereas COX-2 is located in the uterine surface epithelium at preimplantation and in the superficial and deep uterine glands and matrix, and presents a dynamic pattern along the course of gestation.,, In terms of DICs, COX-1-like immunoreactivity was observed in most cell types (with the strongest staining being observed in dMφs), whereas only dMφs and dDCs stained positively for COX-2.,,,,, Moreover, COX-2-generated PGs may participate in DIC recruitment  and alter the cytokine expression profiles of DICs. Data showed that after PGE2 analog administration, dMφ and neutrophil numbers were significantly increased, whereas dNK numbers remained unchanged in first-trimester decidua in humans. Furthermore, major changes occur during Th2/Th1 cytokine production at the maternal–fetal interface during pregnancy. In the uterine and placental tissues, Th2 cytokines, such as interleukin-4 (IL-4) or IL-10, are significantly increased while the production of Th1 cytokines, such as IL-2, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and granulocyte–macrophage colony-stimulating factor (GM-CSF), is decreased; however, pretreatment of DICs with PGE2 modulates IL-2 and GM-CSF production., Moreover, DSCs, trophoblasts, and dMSCs produce PGs, and fortunately, several PG receptors are expressed in DICs, thereby facilitating an intricate immune crosstalk between them. The following sections elucidate the role of COX-2 and its products in DICs with respect to the regulation of the phenotypic and functional characteristics of DICs, particularly focusing on its upstream and downstream signaling cascades.
| Cyclooxygenase-2 and Decidual Macrophages|| |
Nonpregnant endometria contain only a small amount of Mφ; however, the number increases during gestation, accounting for around 20%–30% of all decidual leukocytes.,, In the maternal–fetal interface, dMφs play an indispensable role in implantation, maternal–fetal tolerance, tissue and vascular remodeling, and parturition.,,,,,,, In general, macrophage (Mφ) functions are decided in response to microenvironmental signals that drive the acquisition of polarized programs, whose extremes can be simplified using the M1 and M2 dichotomy: M1, a classically activated Mφ that is microbicidal and inflammatory; and M2, an alternatively activated Mφ that is immunomodulatory and can induce tolerance and the resolution of inflammation., dMφs, which do not follow the conventional M1/M2 categorization, are implicated to be a heterogeneous population of Mφs with diverse phenotypes and functions that facilitate adaptive responses to the ever-changing environment.,, From an immunometabolic perspective, dMφs and peripheral monocytes (pMos) have distinct metabolic profiles, out of which COX-2-catalyzing AA metabolism takes a predominant position, exerting profound influence on modulating the phenotypes and biological functions of dMφs.
Pregnancy can be a proinflammatory or anti-inflammatory condition depending on the gestational stage, and COX-2-generated prostanoids appear to be indispensable in both the inflammatory and anti-inflammatory phases of pregnancy. During early pregnancy, dMφs shift toward the anti-inflammatory M2 polarization, which prevents fetus rejection and allows fetal growth until parturition. Numerous evidences have demonstrated that the proinflammatory lipid mediator PGE2 mediates the polarization of the M2 Mφs,,,,, suggesting the role of PGE2 in dMφ polarization during early pregnancy. Interestingly, PGE2 switches dMφs toward an immunosuppressive phenotype  and upregulates the production of the immunosuppressive cytokine IL-10 in dMφs.,
However, at the onset of the implantation period, dMφs are induced toward inflammatory M1 activation, switched to a mixed M1/M2 profile, and maintained in this mixed phenotype until the early phase of the second trimester. During this stage, some special pregnancy processes occur, including blastocyst implantation, trophoblast invasion, and angiogenesis, which creates a veritable “battleground” of invading, dying, and repairing cells. Naturally, inflammatory dMφs are required to secure the adequate repair of the uterine epithelium and removal of cellular debris. Likewise, parturition (another proinflammatory event) is preceded by an accumulation of M1-type dMφs in the uterus. Previous studies have shown that appropriate COX-2-induced inflammation is a crucial event for both implantation  and initiation of human parturition,,,, which otherwise lead to undesirable pregnancy outcomes.,,,,,,,, However, there are only a handful of studies regarding placenta-derived prostanoids modulating dMφ polarization under such circumstances. During implantation and parturition, dMφs participate via the reprogramming of COX-2-catalyzing AA metabolism and the secretion of diverse prostanoids,,,, thereby facilitating trophoblast invasion, angiogenesis, cervical ripening, and myometrial contraction.
Among all COX-2 products, PGE2 and TXA2 are two of the most dominant products in both peripheral Mφs and dMφs.,, However, only PGE2 concentrations suffer the regulation of special hypoxic conditions in the maternal–fetal interface. Physiological concentrations of progesterone  and pregnancy-specific glycoproteins  stimulate COX-2 activity in dMφs, thereby contributing to the generation of an immune environment compatible with successful pregnancy. PGE2, after binding to different EP receptors, can regulate the function of many cell types, including macrophages, dendritic cells, and T and B lymphocytes, leading to both pro- and anti-inflammatory effects. As a proinflammatory mediator, PGE2 contributes to the regulation of the cytokine expression profile in the uterus and modulation of T cell differentiation.,, On the other hand, PGE2 has also been demonstrated to exert anti-inflammatory actions on innate immune cells such as neutrophils, monocytes, and NK cells as well as on acquired immune cells such as Th1 cells. In the maternal–fetal interface, dMφ-derived PGE2 has been implicated to be a paracrine mediator because PGE2 exerts effects on trophoblastic outgrowth, immunosuppression of T cell alloreactivity,, and proliferation and cytolytic activity of dNKs., TXA2, an unstable AA metabolite, has also been shown to be involved in the modulation of acquired immunity, thereby inducing the chemokinesis of native T cells and impairing DC-T cell adhesion and DC-dependent proliferation of T cells. However, studies on the potential functions of dMφ-derived TXA2 are limited. PGD2, another product of COX-2 in dMφs, appears to function in both inflammatory and homeostatic capacities , and is associated with decidual Th2 cell recruitment and inhibition of DC migration to the deciduas.
Due to high plasticity, abnormal activation of inflammation upregulates COX-2 expression in dMφs and drives M1 dMφ polarization. Infection is one of the leading causes in this polarization process, usually resulting in preterm birth (PTB),,, stillbirth,, and adverse fetal outcomes.,, Data show that infection enhances COX-2 activity in both peripheral tissues , and the maternal–fetal interface., Outside the uterus, reprogramming of the prostanoid metabolism can occur upon cellular differentiation, i.e., while resting Mφs produce TXA2 under excessive PGE2 conditions, the ratio changes to favor PGE2 production after lipopolysaccharide (LPS) activation. Whether such patterns apply to dMφs needs to be further elucidated. A variety of pathogens, such as LPS,, influenza A virus, and Plasmodium, have been reported to upregulate COX-2 expression in dMφs. Notably, placental malaria is highly associated with COX-2 upregulation in dMφs, and an estimated 125 million pregnancies globally are at risk of malaria each year, which causes substantial maternal and infant morbidity/mortality.,,, Plasmodium upregulates the expression of the proinflammatory cytokine, COX-2. However, COX-2 inhibitors can interfere with prostanoid synthesis and modulate the outcome of the pregnancy. Apart from microorganisms, harmful environmental stimuli such as diethylhexyl phthalate, widely used as a plasticizer in polyvinyl chloride products, also activate the expression of COX-2 in dMφs.
However, some studies question the significance of reprogramming COX-2-catalyzing AA metabolism in dMφs because no difference was observed between dMφs and pMos in terms of PGE2 production. In addition, LPS induces dMφs to generate and release the proinflammatory molecules, TNF-α, transforming growth factor-β, and IL-1, but not PGE2. Moreover, COX-2 expression in the placenta was also reported to be unchanged after preeclampsia. Therefore, more evidences are required to clarify these controversies.
| Cyclooxygenase-2 and T Cells, Decidual Natural Killer Cells, and Decidual Dendritic Cells|| |
Although T cells and dNKs do not possess the ability to synthesize prostanoids, dDCs generate a small amount of prostanoids due to the sparse dDC population in the maternal–fetal interface. COX-2-generated prostanoids, particularly PGE2 and PGD2, play a pivotal role in regulating the proliferation, apoptosis, differentiation, and diverse biological functions of T cells, dNKs, and dDCs.
Numerous studies have indicated that PGE2 maintains maternal–fetal tolerance by inducing Th1 cell anergy toward the semiallogeneic fetus.,, Compared to Th1 cells, not only do Th2 cells provide an alternative and potentially less embryo-toxic differentiation state during pregnancy, but also Th2 cytokines have the ability to repress Th1 cell differentiation and function. Therefore, it is preferred if the maternal–fetal interface has a general Th2-bias toward T cell response in order to minimize the generation of Th1 cells. PGE2 interacts with a number of different specific receptors in T cells, some of which elevate the intracellular level of cAMP, thereby leading to anergy. PGE2 specifically interacts with the EP4 receptor and directly affects T cell differentiation by inhibiting the production of Th1 cytokines, including IL-2 and IFN-γ, without affecting the production of the Th2 cytokines, IL-4, IL-5, and IL-10. Besides, PGE2 primes naïve T cells in a dose-dependent fashion to produce high levels of IL-4, IL-10, and IL-13, and very low levels of IL-2, IFN-γ, TNF-α, and TNF-β. Similar to T cells, PGE2 also inhibits the proliferation, cytotoxicity, and IFN-γ production of dNKs,,,, which causes them (CD56+ and CD16−) to exhibit immunosuppressive properties. Downregulation of the surface expression of the γ-chain on NK cells may be a mechanism by which PGE2 mediates the suppression of IL-15-activated NK cell function., Recently, NKs with a phenotype of PTGS2/COX-2 (high) in endometriosis were reported to present impaired cytotoxic activity. Unfortunately, only a few studies on the reprogramming of COX-2-catalyzing AA metabolism in dNKs have been conducted so far. In terms of dDCs, PGE2 blocks DC differentiation,, which is particularly relevant as the presence of mature DCs in placental tissues may induce potentially harmful T cell responses.
PGD2, analogous to PGE2, contributes to successful pregnancies by moderating the Th1/Th2 balance and antigen presentation by DCs via its dual receptor (CRTH2 and DP) system. CRTH2 is an extremely reliable marker for detecting human Th2 and T cytotoxic type 2 (Tc2) cells. Interestingly, CRTH2-expressing T cells are reported to be significantly higher in number in the decidua (especially at the implantation site),, suggesting that Th2 and Tc2 cells are recruited into the maternal–fetal interface via PGD2 mediation.
At the maternal–fetal interface, crosstalk between DSCs, trophoblasts, dMSCs, and DICs serves the prerequisite for successful pregnancies; however, the involvement of DSCs, trophoblasts, and dMSCs complicates the COX-2-catalyzing AA metabolic process in DICs. Although dMφs and DSCs are the main sources of PG, the rate of prostanoid synthesis is higher in dMφs than DSCs. DSCs, trophoblasts,, and dMSCs , have been shown to stimulate COX-2 activity in dMφs. For example, data newly identified significant paracrine interactions between DSCs and dMφs in response to pathogen-associated molecular patterns (PAMP) and microbial immune stimulation, partially due to PGE2. PGE2 was also shown to modulate the inhibitory effect of DSCs with respect to the survival and functions of dNKs and dDCs. Moreover, dMSCs have been reported to secrete the soluble factor, PGE2, to inhibit IL-2-induced dNK proliferation.
| Concluding Remarks|| |
COX-2 and its products play a dual role in both the proinflammatory and anti-inflammatory processes during pregnancy, and abundant evidences indicate special reprogramming of the COX-2-catalyzing AA metabolism in dMφs corresponding to special gestational phases. In general, the uterus favors a semiallogeneic, fetus-friendly environment where prostanoids modulate the dMφ acquisition of immunosuppressive phenotypes and functions. Notably, a rigorously controlled inflammatory state is elicited during implantation and parturition through which COX-2 expression is significantly upregulated in dMφs, followed by prostanoid formation. In contrast, abnormal inflammation, such as those caused by infection, probably induces an uncontrolled COX-2-relevant inflammatory cytokine cascade in dMφs, resulting in undesirable pregnancy outcomes. Similar to the actions in dMφs, prostanoids (PGE2 and PGD2 in particular) serve lipid mediators, thereby regulating the phenotypes and biological functions of T cells, dNKs, and dDCs. Moreover, the involvement of DSCs, trophoblasts, and dMSCs complicates this crosstalk. Considering its versatile functions at maternal–fetal interface, COX-2-catalyzing AA metabolism in DICs may be a new therapeutic target for reproductive disorder and abnormal parturition, such as recurrent implantation failures, abnormal abortion, PTB, and so on.
Even now, the delicate regulatory mechanisms, especially those at the genetic and epigenetic levels, underlying the reprogramming of COX-2-catalyzing AA metabolism in dMφs remain largely unknown, let alone in dDCs and other DIC populations synthesizing prostanoids. With so much emphasis on PGE2, it is also important to note that information on other COX-2 products is also rather limited.
Financial support and sponsorship
This study was supported by the Major Research Program of the National Natural Science Foundation of China (No. 31970798, 31671200, 91542108, and 81471513), Shanghai Rising-Star Program (16QA1400800), Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (CX2017-2), and the Program for Zhuoxue of Fudan University, China.
Conflicts of interest
There are no conflicts of interest.
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