|Year : 2019 | Volume
| Issue : 2 | Page : 110-116
Indoleamine 2,3-dioxygenase in endometriosis
Hui-Li Yang1, Ming-Qing Li2
1 Laboratory for Reproductive Immunology, Insitute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
2 Laboratory for Reproductive Immunology, Insitute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Shanghai 200080; Laboratory for Reproductive Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Shanghai 200011; Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 230032, China
|Date of Submission||05-Jan-2019|
|Date of Web Publication||9-Jul-2019|
Dr. Ming-Qing Li
Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Lane1326, Pingliang Road, Shanghai 200080
Source of Support: None, Conflict of Interest: None
Endometriosis (EMS) is a chronic inflammatory and estrogen-dependent gynecological disease characterized by the presence of endometrial tissue outside the uterine cavity. Although it is a benign disease, EMS is tumor-like in several aspects, which include unrestrained growth, decreased apoptosis, and aggressive invasion. EMS involves endocrine disorders and immunological factors. Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the initial and rate-limiting step of the metabolism of tryptophan. IDO is a potential candidate facilitating EMS development. Increased IDO expression in both eutopic and ectopic endometria of women with EMS is biologically important in aspects, which include regulation of endometrial stromal cell function and modulation of adjacent local immunocytes to generate a supportive microenvironment. In turn, the expression of IDO can be regulated by the complex endocrine-immune microenvironment networks in endometrial lesions. Here, we systematically review the roles of IDO in EMS to explore its pathological implications and treatment potential.
Keywords: Endometrial Stromal Cells; Endometriosis; Immunocytes; Indoleamine 2,3-Dioxygenase
|How to cite this article:|
Yang HL, Li MQ. Indoleamine 2,3-dioxygenase in endometriosis. Reprod Dev Med 2019;3:110-6
| Introduction|| |
Endometriosis (EMS) is a benign, chronic, and estrogen-dependent gynecological disease characterized by the presence of endometrial tissue outside the uterine cavity. EMS causes pelvic pain, dyspareunia, and infertility in women of reproductive age. The causes of EMS are complicated and not thoroughly clear. The theory of retrograde menstruation is widely accepted. Approximately 76%–90% of women experience retrograde menstruation, whereas only 6%–10% of women develop EMS. Thus, the pathogenesis of EMS cannot be determined from the endocrine perspective alone. Multiple factors participate in the development and maintenance of EMS. Women with EMS have been reported to have a biochemical, genetic, or immunological dysfunction that prevents removal of endometrial tissues from the peritoneal cavity and facilitates tissue adhesion to extrauterine structures.
As a tumor-like benign disease, EMS is similar to cancer in several aspects, such as unrestrained growth, decreased apoptosis, and aggressive invasion. This indicates that a microenvironment of immune tolerance is formed within ectopic lesions in patients with EMS, wherein the clearance of menstrual debris by the local immune responses is ineffective. Progressive growth of ectopic tissues relies on defects of the immune system in addition to genetic and epigenetic predispositions, which allow endometrial stromal cells (ESCs) to escape apoptosis, evade immune surveillance, invade the mesothelial surface, and acquire a vascular supply., Data from our and others' labs have revealed that the dysfunction of immune cells in the microenvironment of the peritoneal cavity or ectopic lesions, including neutrophils, macrophages, natural killer (NK) cells, dendritic cells, T helper cells, and B cells, contributes to the pathogenesis and progression of EMS.,,,,
Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the initial and rate-limiting step of the metabolism of tryptophan, an essential amino acid, in the kynurenine pathway. IDO catalyzes the metabolism of tryptophan into N-formylkynurenine and kynurenine. The IDO family consists of two enzymes: IDO1 and IDO2. The IDO2 appears to be functional only in mice, not in humans. IDO is expressed by a large variety of cells, including lymphocytes (dendritic cells, macrophages, and B cells), human tumor cell lines, endothelial cells, and stromal cells. IDO1 has been conclusively identified as an immune modulator through tryptophan metabolism and via the generation of proapoptotic metabolites., For instance, IDO1 overexpression can induce the exhaustion of local tryptophan and metabolites of the kynurenine pathway, which produces immunosuppressive effects on immune cells. In recent decades, IDO1 has been shown in numerous studies to produce a marked tolerance effect in organ transplantation, fetal rejection, autoimmune disorders, and cancer.
IDO1 is considered a potential candidate that facilitates the development of EMS. Burney et al. and Aghajanova et al. described the increased IDO1 gene expression in EMS-derived eutopic endometrium and its relevance to the patients' clinical stage. Our results also revealed the expression of IDO1 in the stromal cells of the endometrium or endometriotic tissues and the pronounced expression in EMS-derived ESCs.
With a deep understanding of EMS, especially from the perspective of immunity, considerable evidence supports the concept that IDO contributes to the occurrence and development of this gynecological tumor-like disease. In this review, we discuss the expression of IDO in the endometrium and endometriotic lesions and elucidate the role of IDO in EMS.
| Indoleamine 2,3-Dioxygenase in Normal Endometrium and Endometriotic Lesions|| |
It has reported that IDO1 was expressed in the human female genital tract. Endometrial glandular and surface epithelial cells showed increasing IDO expression during the menstrual cycle. Subsequently, transcripts of IDO1 were detected in the endometrium of nonpregnant women and rhesus monkeys., Using Western blotting and immunohistochemistry, Jeddi-Tehrani et al.obtained evidence that IDO protein is synthesized in the endometrium of cycling mice throughout the estrous cycle. IDO protein was mainly localized in the glandular and luminal epithelial cells [Table 1]. These results support the idea that IDO provides a mechanism of innate immunity to protect from ascending infections in the female reproductive tract. In addition, taking the fact that mating only occurs during the estrous phase into account, the high expression of IDO in this phase is likely to be a mechanism that induces immune tolerance of the fetus. IDO1 transcript levels are likely associated with species-specific aspects of reproduction. Higher transcript levels of IDO1 in the uterus of mice were detected during estrous than during the remaining phases of the cycle. In contrast, IDO1 expression in the endometrium of women was increased during the secretory phase and was barely expressed in the proliferative phase of the normal endometrium. However, IDO1 protein expression was stable over the endometrial cycle in equine endometrium.
|Table 1: IDO1 expression in normal endometrium and endometriotic lesions|
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In the endometrium of cycling mice, IDO protein was mainly localized in the glandular and luminal epithelial cells. Our previous work demonstrated that IDO1 was expressed in glandular endometrium, surface epithelial cells, and stromal cells of human endometrium. Immunohistochemical detection of IDO1 in the endometria of 25 mares demonstrated that the immune-positive cell populations comprised epithelial cells, macrophages, intravascular monocytes, and neutrophils. More recently, we found that NK cells in peritoneal fluid (PF) from women with or without EMS can express IDO1.
Human endometriotic tissues display a high kynurenine/tryptophan ratio, compared with control tissues. The ratio is also an index for IDO1 activity. In the eutopic endometrium from women with EMS, microarray analysis detected higher levels of IDO1 compared with normal endometrium and was relevant to the patients' clinical stage., In our study, IDO1 was present in the stromal cells of endometrium or endometriotic tissues, and especially was highly expressed in EMS-derived eutopic and ectopic ESCs compared with healthy eutopic ESCs. Menstrual blood-derived stromal stem cells from women with EMS (E-MenSCs) produced higher amounts of IDO1 at the gene and protein levels. Consistently, IDO1 activity in the supernatant of coculture system of E-MenSCs and peripheral blood mononuclear cells (PBMCs) was shown to be superior to that of the control. However, relatively low IDO1 expression was shown specifically in equine endometriotic glands. In endometria of mares with EMS, endometriotic glands were IDO1 immune-negative or were lined by only a few weakly immune-positive epithelial cells.
| Roles of Indoleamine 2,3-Dioxygenase in Endometriosis|| |
Regulation of endometrial stromal cell biological behaviors
Biological behaviors of ESCs, including proliferation, autophagy, apoptosis, adhesion, and invasion, are closely associated with the pathogenesis of EMS.,, Eutopic and ectopic ESCs from EMS patients expressed a higher level of matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 (COX-2) than the normal group. Due to an altered production of MMPs in the eutopic endometrium from women with EMS, the retrograde endometrial tissue could be more prone to peritoneal implantation and invasion. COX-2 and its derivative, prostaglandin estradiol (E2), play key roles in the origin and development of EMS through increased migration and invasiveness., Stimulation with IDO1 has been shown to trigger the expression of MMP-9 and COX-2 in normal and eutopic ESCs. The IDO1 promoter contains motifs of transcription factor metalloendopeptidase-1, which can directly regulate the transcription of MMP genes. Levo-1-methyl-tryptophan (L-1-MT), a specific inhibitor of IDO1, could reverse COX-2 upregulation triggered by lipopolysaccharide (LPS), which strongly suggests an intrinsic correlation between IDO1 and COX-2. L-1-MT could enhance decidualization in ESCsin vitro evidenced by increased prolactin (PRL) and decrease ESC survival. Moreover, L-1-MT suppressed the adhesion and invasion of ESCs. Specifically, L-1-MT could abolish the increased adhesion capability of ESCs induced by LPS in Type I collagen, Type IV collagen, fibronectin, and fibrinogen. However, individual L-1-MT treatment had no effect on the initial attachment of ESCs derived from the normal control and from the eutopic group. These results indicate that inducible IDO1 expression is an important and determinant way, in which ESCs interact with the extracellular environment in vitro, but that the intrinsic IDO1 is inadequate to impact the adhesion of ESCs. Consistently, we found that IDO1 overexpression in ESCs elevated cell invasiveness compared to that of normal ESCs. Overexpression of IDO1 in normal ESCs elicited an increase in the phosphorylation of the c-Jun N-terminal kinase (JNK) signaling pathway. IDO1 could downregulate the expression of p53, as well as the apoptosis of ESCs through the JNK pathway. Moreover, administration of JNK inhibitor could abolish the increased invasion capability and the expressions of MMP-9 and COX-2 in ESCs induced by IDO1. Therefore, the enhancement of invasion of ESCs due to MMP-9 and COX-2 secreted from IDO1-stimulated ESCs may be activated in the disease of ESCs via the JNK pathway, although further studies are needed to reinforce this suggestion. In addition, higher proliferation and invasion capacity of E-MenSCs could also be in part related to the higher IDO1 level and activity.
Macrophages are the dominant immune cells recruited to the PF from PBMCs to remove the retrograde endometrial debris. Several studies have indicated that the pelvic macrophages seem to polarize to the M2 state, which displays the alternatively activated phenotype with anti-inflammatory characteristic., In EMS, the inactivation of PF macrophages with respect to cytotoxicity and phagocytosis of refluxed endometrial tissue has been previously reported.
The crosstalk between ESCs and macrophages has been suggested to contribute to the immune dysfunction of the endometriotic microenvironment. The ectopic ESCs with higher IDO1 expression markedly inhibited the phagocytic capacity of cocultured macrophages and significantly downregulated antigen-presenting molecules, such as human leukocyte antigen-antigen D related and cluster of differentiation (CD) 11c. Conversely, ectopic ESCs promoted M2 phenotypic markers (CD163 and CD209) and intracellular M2 cytokine bias, such as low-level interleukin (IL)-23, high-level IL-10, and transforming growth factor (TGF)-β1, compared to normal ESCs. The IDO1-induced IL-33 secretion in ectopic ESCs might participate in the macrophage polarization of EMS. IDO1 interference of ectopic ESCs could partly impair the effect induced by ectopic ESCs. This implicates IDO1 as a candidate molecule, but definitely not the only one, leading to the induction of macrophage tolerance during ESC-macrophage interaction, thereby participating in the impairment of peritoneal macrophage in EMS. When cocultured with macrophages pretreated with IDO1-overexpressing ESCs, compared with macrophages treated with normal ESCs, the viability and proliferation of ESCs were significantly increased and apoptosis index decreased, suggesting that high levels of IDO1 expressed in the ectopic environment may induce the formation of tolerant macrophages, which, in turn, could promote ectopic ESC growth in the progression of EMS.
Natural killer cells
NK cells are one of the most important cellular components of PF. Cytokines change the milieu in the peritoneal cavity of patients with EMS and thus diminish the cytotoxic activity of NK cells, which is indispensable for the initiation and development of EMS., We have found that NK cells in PF from women with EMS highly express IDO. IDO+ NK cells present lower levels of NKp46 and NKG2D, but higher IL-10 than that of IDO− NK cells. Furthermore, ESCs, especially ectopic ESCs, significantly upregulated IDO levels in NK cells, which was partly dependent on TGF-β. IDO might impair the cytotoxicity of NK cells by suppressing NKG2D and NKp46 and enhancing IL-10, resulting in the poor clearance of ectopic ESCs and finally contributing to the formation of ectopic endometrial lesions.
Tissue-resident mast cells (MCs) are recognized as effector cells in many settings of the immune response, including immune regulation, allergy, host defense, chronic inflammation, and autoimmune diseases. MCs are capable of orchestrating inflammation by modulating the recruitment and function of other immune cells, which have been reported to be involved in EMS pathogenesis., Diffuse infiltration of degranulated tryptase-positive MCs was observed throughout endometriotic stromal lesions and was often close to nerve fibers., A study recently discovered that the aryl hydrocarbon receptor (AhR), a transcription factor expressed in multiple tissues and in immune cells, modulated acute and late MC responses. A number of chemicals are endogenous or physiological AhR ligands. These include tryptophan products. It has been reported that endometrium-resident AhR-activated MCs, which represent an early source of IL-10, could also promote peritoneal M2 macrophage polarization into a phenotype possessing tolerogenic activity. In EMS, human endometriotic tissue was reported to be rich in IDO1 and the AhR-ligand kynurenine compared with control tissue and was conducive to cytokine production, orchestrating chronic inflammation, and a population of AhR-expressing MCs that were IL-17 and IL-10 positive. High levels of kynurenine induced by increased IDO1 in endometriotic tissue possibly promoted MC activation through AhR. Moreover, endometriotic tissue was susceptible to treatment with an AhR antagonist, and ESC growth was improved in the presence of soluble factors released by MCs upon AhR activation.
Regulatory T cells
IDO1 catalyzes the metabolism of tryptophan, an amino acid that is essential for T cell proliferation and differentiation. IDO1 suppresses T cell responses, promotes immune tolerance, and influences the differentiation of regulatory T (Treg) cells. In EMS, peritoneal Treg cells increase in number as the disease progresses. The percentage of Treg cells in the PF of EMS patients is higher than that in healthy women, and the augmentation of Treg cell percentage, especially that of TGF-β1+ Treg cells, occurs in parallel with EMS exacerbation., Endometriotic microenvironment is affected by changes in the proportion of Treg cells, which, in turn, plays a vital role in the maintenance of immune homeostasis to prevent potentially severe autoimmunity., We have found that the estrogen-IDO1-mannose receptor C, Type 2 (MRC2) axis, participated in the differentiation and function of Treg. 1-MT could inhibit Treg cell differentiation, especially that of IL-10+ Treg cells, indicating that IDO1 participates in the differentiation of Treg cells in ectopic lesions. In addition, 1-MT was involved in the suppression of Treg cells. 1-MT-pretreated ESC-educated Treg cells suppressed the proliferation of Teff (effector T) cells less effectively compared with nontreated ESC-educated Treg cells.
| Regulatory Factors of Indoleamine 2,3-Dioxygenase in Endometriosis|| |
IDO normally has low basal expression, but is rapidly induced by inducer of interferon (IFN)-γ alone or synergized with other proinflammatory stimuli, including tumor necrosis factor-alpha, IL-1β, and LPS in specific cell types. Proinflammatory cytokines were also highly expressed in ectopic lesions and PF from women with EMS., Therefore, these proinflammatory cytokines may also contribute to the high level of IDO in endometriotic lesions and EMS-derived ESCs, suggesting another possible link between inflammation and the development of EMS. The striking increase in kynurenine content in endometriotic tissues compared with controls is consistent with the abundance of inflammatory cytokines observed and in other diseases in which the immune response is activated and IFN-γ is produced., Higher amounts of IFN-γ and monocyte chemoattractant protein-1 (MCP-1) were detected in E-MenSCs-PBMC cocultures. Higher IFN-γ production by monocytes and macrophages, which might result from higher concentration of MCP-1, should be the reason for the upregulated IDO1 expression in E-MenSCs. In addition, the aberrant expression of IDO1 in eutopic endometrium could be enhanced by LPS via inflammatory mechanism and inhibited by L-1-MT.
Apart from inflammation factors, several proteins that exist in ectopic lesions are secreted from ESCs, which may also regulate IDO1 production and activation. Increased IDO1 induction in the eutopic endometrium might be due to a slightly higher level of CD200, a Type I transmembrane anchored glycoprotein that is structurally similar to immunoglobulins. The CD200 tolerance signaling molecule has been reported to promote Treg cells and promote IDO-production by macrophages., The effect of ESCs on upregulating the expression of IDO1 in macrophages was more significant than that with estrogen alone, indicating crosstalk between ESCs and macrophages related to IDO1 expression. The crosstalk between ESCs and macrophages has been reported to impair the cytotoxicity of NK cells by secreting IL-10 and TGF-β in EMS. In addition, ectopic ESCs led to a high level of IDO in NK cells partly by secreting a high level of TGF-β. Given that TGF-β1 was reported to induce the phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in IDO and the expression of Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2 via Smad and phosphoinositol-3-kinase-dependent pathways, ESC-derived TGF-β may regulate the expression of IDO in endometrial NK cells and ITIMs in IDO may inhibit NK cells-mediated cytolytic activity through SHP-2, which negatively regulates NK cell function.,
EMS is a hormone responsive disease associated with increased levels of estrogen. Increased expression of estrogen receptors (ER) α and β has been observed in ectopic tissue compared with normal and eutopic endometrium. As introduced previously, estrogen-IDO1-MRC2 axis is involved in the differentiation and function of Treg cells in EMS. IDO1 expression in estrogen-conditioned ESCs and estrogen-conditioned macrophages was obviously higher than that in the control groups, suggesting that IDO1 is upregulated by estrogen in ectopic lesions. Both subunits of ER are involved in this activity, especially ERβ. Hence, estrogen promotes the differentiation of Treg cells via upregulation of IDO1 expression. Engelholm et al. reported that mannose receptor C, Type 2 (MRC2), a constitutively recycling endocytic receptor belonging to the mannose receptor family, was downstream to estrogen and IDO1. High levels of IDO1 might lead to the low expression of MRC2 in ectopic ESCs. After silencing MRC2 in ESCs, the expression of IDO1 increased. This result suggests that there is a negative feedback between MRC2 and IDO1.
| Conclusions and Perspectives|| |
EMS is more than a disease involving endocrine disorders. It also involves immunological factors. Increased IDO1 protein expression in eutopic and ectopic endometria of women with EMS has biological importance. It can directly promote the proliferation and invasion of endometrial tissue by regulating the function of ESCs [Figure 1], and can modulate adjacent immunocytes, including macrophages, NK cells, Treg cells, and MCs, to generate a supportive microenvironment [Figure 2]. These effects finally lead to the formation of endometriotic lesions and the abnormal decidualization of the endometrium.
|Figure 1: Summary of biological functions of IDO1 in ESCs. IDO1 can directly promote the survival and proliferation of ESCs. IDO1 could downregulate the expression of p53 and enhance the expressions of MMP-9 and COX-2 in ESCs via JNK pathway, contributing to ESC suppression of apoptosis and promotion of invasion respectively. By downregulating PRL expression, IDO1 could also inhibit decidualization in ESCs in vitro. Moreover, IDO1 may enhance adhesion capability of ESCs by upregulating Type I collagen, Type IV collagen, fibronectin, and fibrinogen. IDO: Indoleamine 2,3-dioxygenase; ESC: Endometrial stromal cell; JNK: c-Jun N-terminal kinase; MMP-9: Matrix metalloproteinase-9; COX-2: Cyclooxygenase-2.|
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|Figure 2: Schematic representation of the effects of IDO1 on immune cells and ESC function modulation of the supportive microenvironment generated by immunocytes in EMS. The crosstalk of IDO1-positive ESCs and immunocyte finally leads to the formation of endometriotic lesions and the development of EMS. (1) IDO1-induced IL-33 in ESCs might inhibit the phagocytic capacity of macrophages, significantly downregulate antigen-presenting molecules and promote M2 phenotype polarization. These tolerant macrophages could in turn promote ESC proliferation and inhibit ESC apoptosis. (2) High levels of kynurenine induced by increased IDO1 in ESC possibly promotes MC activation (IL-10 and IL-17 positive) through AhR. IL-10 derived from endometrium-resident AhR-activated MCs could promote peritoneal M2 macrophage polarization and soluble factors released by MCs upon AhR activation could promote ESC growth. (3) ESCs could significantly upregulate IDO levels in NK cells, which is partly dependent on TGF-β. IDO might impair the cytotoxicity of NK cells by suppressing NKG2D and NKp46 and enhancing IL-10, resulting in the immune escape of ESCs. (4) Downregulated MRC2 by IDO1 in ESCs could participate in the differentiation IL-10+ Treg cells, which could suppress the proliferation of Teff cells. IDO: Indoleamine 2,3-dioxygenase; ESC: Endometrial stromal cell; EMS: Endometriosis; IL: Interleukin; MCs: Mast cells; NK: Natural killer; TGF-β: Transforming growth factor-β; MRC2: Mannose receptor C, Type 2; Teff: Effector T.|
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IDO1 expression can be regulated by the endocrine condition characterized by elevated estrogen and also by immunological factors that include proinflammatory stimuli, such as IFN-γ and LPS, and anti-inflammatory cytokines that include TGF-β. In addition, several modulators in ectopic lesions, such as CD200 and MRC2, can regulate the expression of IDO1. Thus, IDO1 is involved in the information and maintenance of both the endocrine and immune microenvironment of ectopic lesions in EMS. In turn, the expression and function of IDO1 is regulated by complex endocrine-immune microenvironment networks. This information will be helpful for further investigation of the pathogenesis of EMS. However, whether increased IDO1 in eutopic and ectopic endometria of women with EMS precedes the development of disease or results afterward from development of ectopic lesions is still unclear. Further studies, especially using animal models, should be established to increase knowledge of IDO1 participation in the pathophysiology of EMS.
1-MT is also undergoing clinical Phase I and II trials concerning cancer immunotherapy. The collective potential of IDO1 highlights the importance of exploring IDO1-based therapies for EMS. One example is an intrauterine device system capable of releasing 1-MT for the prevention and treatment of EMS. This and other IDO1-based therapies must not disrupt the hormonal balance. In vivo, the ESCs are exposed to autologous immune cells and complex interactions exist between ESCs and immune cells. Therefore, assessments of the local immunological status of patients with EMS are essential to guide the treatment choice. Our previous studies have implied a special immune microenvironment (coexistence of proinflammatory and anti-inflammatory factors) in the endometriotic milieu. The potential value of 1-MT treatment targeting IDO1 for EMS patients with immune imbalancein vivo requires further research and exploration.
Financial support and sponsorship
This study was supported by the Major Research Program of National Natural Science Foundation of China (No. 91542108, 81471513, and 31671200), the Shanghai Rising-Star Program 16QA1400800, the Innovation-oriented Science and Technology Grant from National Population and Family Planning Commission 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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[Figure 1], [Figure 2]