IDO Expression in Cancer: Different Compartment, Different Functionality?
Meireson Annabel,Devos Michael,Brochez Lieve
Frontiers in immunology
Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.
10.3389/fimmu.2020.531491
The emerging roles of IDO2 in cancer and its potential as a therapeutic target.
Li Pengcheng,Xu Weiqi,Liu Furong,Zhu He,Zhang Lu,Ding Zeyang,Liang Huifang,Song Jia
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
During the past decades, tryptophan metabolism disorder was discovered to play a vital and complex role in the development of cancer. Indoleamine 2,3-dioxygenase 2 (IDO2) is one of the initial and rate-limiting enzymes of the kynurenine pathway of tryptophan catabolism. Increasing evidence indicates that IDO2 is upregulated in some tumors and plays a role in the development of cancer. In spite of the growing body of research, few reviews focused on the role of IDO2 in cancer. Here, we review the emerging knowledge on the roles of IDO2 in cancer and its potential as a therapeutic target. Firstly, the main biological features and regulatory mechanisms are reviewed, after which we focus on the expression and roles of IDO2 in cancer. Finally, we discuss the potential of IDO2 as a therapeutic target for cancer treatment.
10.1016/j.biopha.2021.111295
Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion.
Muller Alexander J,DuHadaway James B,Chang Mee Young,Ramalingam Arivudinambi,Sutanto-Ward Erika,Boulden Janette,Soler Alejandro P,Mandik-Nayak Laura,Gilmour Susan K,Prendergast George C
Cancer immunology, immunotherapy : CII
Indoleamine 2,3-dioxygenase (IDO) is generally considered to be immunosuppressive but recent findings suggest this characterization oversimplifies its role in disease pathogenesis. Recently, we showed that IDO is essential for tumor outgrowth in the classical two-stage model of inflammatory skin carcinogenesis. Here, we report that IDO loss did not exacerbate classical inflammatory responses. Rather, IDO induction could be elicited by environmental signals and tumor promoters as an integral component of the inflammatory tissue microenvironment even in the absence of cancer. IDO loss had limited impact on tumor outgrowth in carcinogenesis models that lacked an explicit inflammatory tumor promoter. In the context of inflammatory carcinogenesis where IDO was critical to tumor development, the most important source of IDO was radiation-resistant non-hematopoietic cells, consistent with evidence that loss of the IDO regulatory tumor suppressor gene Bin1 in transformed skin cells facilitates IDO-mediated immune escape by a cell autonomous mechanism. Taken together, our results identify IDO as an integral component of 'cancer-associated' inflammation that tilts the immune system toward tumor support. More generally, they promote the concept that mediators of immune escape and cancer-associated inflammation may be genetically synonymous.
10.1007/s00262-010-0891-4
Exploitation of the IDO Pathway in the Therapy of Rheumatoid Arthritis.
Williams Richard O
International journal of tryptophan research : IJTR
Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting step along the kynurenine pathway and is thought to play a key role in immune homeostasis through depletion of tryptophan and accumulation of kynurenines. In this review we summarize recent research into the possibility of harnessing the IDO pathway for the therapy of rheumatoid arthritis. Inhibition of IDO activity, or knockout of the gene encoding IDO, was shown to cause an increase in the severity of collagen-induced arthritis, an animal model of rheumatoid arthritis. The increased severity of disease was associated with elevated numbers of pathogenic Th1 and Th17 cells in the joints and draining lymph nodes. In another study, analysis of the kinetics of expression of downstream kynurenine pathway enzymes during the course of arthritis revealed a potential role for tryptophan metabolites in resolution of arthritis. Furthermore, the therapeutic administration of L-kynurenine or [3,4-dimethoxycinnamonyl]-anthranilic acid (a synthetic derivative of 3-hydroxy-anthranilic acid) significantly reduced both clinical and histological progression of experimental arthritis. These findings raise the possibility of exploiting the IDO pathway for the therapy of autoimmune disease.
10.4137/IJTR.S11737
Discovery of the First Potent IDO1/IDO2 Dual Inhibitors: A Promising Strategy for Cancer Immunotherapy.
He Xin,He Guangchao,Chu Zhaoxing,Wu Huanhuan,Wang Junjie,Ge Yiran,Shen Hui,Zhang Shan,Shan Jinxi,Peng Kewen,Wei Zhifeng,Zou Yi,Xu Yungen,Zhu Qihua
Journal of medicinal chemistry
Indoleamine 2,3-dioxygenase-1 (IDO1) plays an important role in tumor immune escape. However, unsatisfactory clinical efficacies of selective IDO1 inhibitors have impeded their further development, suggesting that they do not exert sufficient antitumor effects by selectively inhibiting IDO1. IDO2, an isoenzyme of IDO1, is overexpressed in some human tumors, and emerging evidence suggests that concomitant inhibition of IDO1/2 may have synergistic effects in cancer treatment, revealing a promising cancer immunotherapeutic strategy. Herein, we describe the discovery of compound , the first inhibitor targeting both IDO1/2 that has excellent inhibitory activity (IDO1 IC = 28 nM and IDO2 IC = 144 nM). Notably, (TGI = 69.7%) exhibited significantly stronger antitumor potency than epacadostat (TGI = 49.4%) in CT26 xenograft mouse models, highlighting the advantages of IDO1/2 dual inhibitors for tumor immunotherapy. Preliminary mechanistic studies further identified that exerts its antitumor effect by inhibiting IDO1/2.
10.1021/acs.jmedchem.1c01305
Trial watch: IDO inhibitors in cancer therapy.
Le Naour Julie,Galluzzi Lorenzo,Zitvogel Laurence,Kroemer Guido,Vacchelli Erika
Oncoimmunology
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", which converts the essential amino acid tryptophan (Trp) into the immunosuppressive metabolite kynurenine (Kyn). While expressed constitutively by some tissues, IDO1 can also be induced in specific subsets of antigen-presenting cells that ultimately favor the establishment of immune tolerance to tumor antigens. At least in part, the immunomodulatory functions of IDO1 can be explained by depletion of Trp and accumulation of Kyn and its derivatives. In animal tumor models, genetic or pharmacological IDO1 inhibition can cause the (re)activation of anticancer immune responses. Similarly, neoplasms expressing high levels of IDO1 may elude anticancer immunosurveillance. Therefore, IDO1 inhibitors represent promising therapeutic candidates for cancer therapy, and some of them have already entered clinical evaluation. Here, we summarize preclinical and clinical studies testing IDO1-targeting interventions for oncologic indications.
10.1080/2162402X.2020.1777625
Expression profile of the human IDO1 protein, a cancer drug target involved in tumoral immune resistance.
Vigneron Nathalie,van Baren Nicolas,Van den Eynde Benoît J
Oncoimmunology
Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO1) is a physiological immunoregulatory mechanism often hijacked by tumors. Our recent extensive study of IDO1 protein expression in human tissues showed expression in mature dendritic cells and in pulmonary and placental endothelial cells. IDO1 was also expressed in 56% of tumors, either by tumoral, stromal, or endothelial cells. These results and reagent will guide the clinical development of IDO1 inhibitors for cancer therapy.
10.1080/2162402X.2014.1003012
Recent discovery of indoleamine-2,3-dioxygenase 1 inhibitors targeting cancer immunotherapy.
Weng Tianwei,Qiu Xiaqiu,Wang Jubo,Li Zhiyu,Bian Jinlei
European journal of medicinal chemistry
There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.
10.1016/j.ejmech.2017.11.088
HIV-1 Tat - TLR4/MD2 interaction drives the expression of IDO-1 in monocytes derived dendritic cells through NF-κB dependent pathway.
Bahraoui Elmostafa,Serrero Manutea,Planès Rémi
Scientific reports
In the present study we showed that HIV-1 Tat protein stimulated the expression of Indoleamine 2,3 dioxygenase (IDO) -1 in human monocytes derived dendritic cells (MoDC) but not IDO-2 by acting directly at the cell membrane level. This induction of IDO-1 is dependent on the secondary structure of Tat protein, since stimulation with a chemically oxidized Tat protein loses its capacity to induce the production of IDO-1. Among the variety of candidate receptors described for Tat, we demonstrated that Tat protein interacted physically with TLR4/MD2 complex. Strikingly, blockade of Tat-TLR4 interaction by anti-TLR4 antibodies (clone HTA125), LPS-RS, a known TLR4 antagonist, or by soluble recombinant TLR4/MD2 complex inhibited strongly or totally the capacity of Tat to induce IDO-1 in MoDC while such treatments had no effect on IFN-γ-induced IDO-1. Furthermore, we showed that the activation of the transcription factor NF-κB by Tat is essential for the production of IDO-1 by human MoDC. Indeed, Tat activated NF-κB pathway in MoDC as demonstrated by the phosphorylation of p65 in Tat-treated MoDC. Further, we demonstrate that the stimulation of IDO-1 by Tat or by IFN-γ was totally or partially inhibited in the presence of NF-κB inhibitor respectively. These results suggest that Tat and IFN-γ act probably by two distinct mechanisms to induce the production of IDO-1. Our results clearly demonstrated that, although TLR4 pathway is necessary for Tat-induced IDO-1 in MoDC, it seems not to be sufficient since stable transfection of a functional TLR4/MD2 pathway in HEK or HeLa cell lines which are endogenously defectives for TLR4, did not restore the capacity of Tat to induce IDO-1 while IFN-γ treatment induces IDO-1 in HeLa cells independently of TLR4 pathway. These results suggest the involvement of additional stimuli in addition to TLR4 pathway which remain to be identified. Altogether our results demonstrated that, in human MoDC, HIV-1 Tat protein induced IDO-1 expression and activity in a NF-κB dependent-manner by recruiting TLR4 pathway.
10.1038/s41598-020-64847-y
Increased Expression of Indoleamine 2,3-Dioxygenase (IDO) in Vogt-Koyanagi-Harada (VKH) Disease May Lead to a Shift of T Cell Responses Toward a Treg Population.
Zhang Liming,Huang Yang,Cui Xiaoxiao,Tan Xiao,Zhu Ying,Zhou Wenjun,Wang Chaokui,Yuan Gangxiang,Cao Qingfeng,Su Guannan,Kijlstra Aize,Yang Peizeng
Inflammation
Previous studies have pointed out that indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme initiating tryptophan metabolism, plays a role in the regulation of the immune system. This project was designed to investigate the potential role of IDO in monocyte-derived dendritic cells (moDCs) obtained from active Vogt-Koyanagi-Harada (VKH) disease patients. In this study, we found that the IDO mRNA expression and enzyme activity were increased in active VKH patients as compared with healthy controls and patients in remission. To investigate the role of IDO in immune regulation, an effective inhibitor 1-methyl-L-tryptophan (1-MT) was used to suppress its activity in DCs. The results showed that inhibition of IDO with 1-MT significantly decreased the expression of DC marker CD86. IDO inhibition did not affect the cytokine production of IL-6, IL-1β, TNF-α, IL-10, and TGF-β in DCs. Downregulation of IDO in DCs also led to the reduction of regulatory T (Treg) cells and an increased CD4 T cell proliferation. Treatment with 1-MT did not affect the phosphorylation of the MAPK pathway in DCs. In general, our study suggests that IDO may play an important role in the pathogenesis of VKH disease by regulating DC and CD4 T cell function. Tryptophan deficiency and kynurenine accumulation may account for the complicated effects of IDO. Further research is needed to study the precise tryptophan metabolites that may limit immune responses in VKH disease.
10.1007/s10753-020-01252-7
Immunohistochemical Features of Indoleamine 2,3-Dioxygenase (IDO) in Various Types of Lymphoma: A Single Center Experience.
Kim Mee-Seon,Park Tae In,Son Shin-Ah,Lee Hyoun Wook
Diagnostics (Basel, Switzerland)
Indolamine-2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes amino acid tryptophan to L-kynurenine. IDO is overexpressed in various cancers and several IDO inhibitors have been assessed in multiple clinical trials. If an IDO inhibitor is to be commercialized, IDO immunohistochemistry will be an important method. In this study, 80% (28/35) of mature T- and natural killer (NK)-cell neoplasms showed positivity for IDO protein (score 1: five, score 2: one, score 3: seven, score 4: fifteen). In addition, 29.9% (23/77) of mature B-cell lymphomas showed positivity for IDO protein (score 1: three, score 2: tewelve, score 3: four, score 4: four). In mature B-cell lymphomas, 95.7% (22/23) of IDO positive cases were diffuse B-cell lymphomas. Our study includes various types of lymphoma that were previously unreported and shows various patterns of IDO stain according to the type. When the results are accumulated, IDO immunohistochemistry will be a useful tool to diagnose lymphomas and to predict their prognosis.
10.3390/diagnostics10050275
Interferon-γ enhances the immunosuppressive ability of canine bone marrow-derived mesenchymal stem cells by activating the TLR3-dependent IDO/kynurenine pathway.
Molecular biology reports
BACKGROUND:The immunomodulatory function of mesenchymal stem cells (MSCs) has been considered to be vital for MSC-based therapies. Many works have been devoted to excavate effective strategies for enhancing the immunomodulation effect of MSCs. Nonetheless, canine MSC-mediated immunomodulation is still poorly understood. METHODS AND RESULTS:The inflammatory microenvironment was simulated through the employment of interferon-γ (IFN-γ) in a culture system. Compared with unstimulated cBMSCs, IFN-γ stimulation increased the mRNA levels of Toll-like receptor 3 (TLR3) and indoleamine 2, 3-dioxygenase 1 (IDO-1), and simultaneously enhanced the secretion of immunosuppressive molecules, including interleukin (IL)-10, hepatocyte growth factor (HGF), and kynurenine in cBMSCs. IFN-γ stimulation significantly enhanced the ability of cBMSCs and their supernatant to suppress the proliferation of murine spleen lymphocytes. Lymphocyte subtyping evaluation revealed that cBMSCs and their supernatant diminished the percentage of CD3CD4 and CD3CD8 lymphocytes compared with the control group, with a decreasing CD4/CD8 ratio. Notably, exposure to IFN-γ decreased the CD4/CD8 ratio more effectively than unstimulated cells or supernatant. Additionally, IFN-γ-stimulation increased the mRNA levels of the Th1 cytokines TNF-α, and remarkably decreased the mRNA level of the Th2 cytokine IL-4 and IL-10. CONCLUSION:Our findings substantiate that IFN-γ stimulation can enhance the immunomodulatory properties of cBMSCs by promoting TLR3-dependent activation of the IDO/kynurenine pathway, increasing the secretion of immunoregulatory molecules and strengthening interactions with T lymphocytes, which may provide a meaningful strategy for the clinical application of cBMSCs in immune-related diseases.
10.1007/s11033-022-07648-y
IDO activation, inflammation and musculoskeletal disease.
Ogbechi Joy,Clanchy Felix I,Huang Yi-Shu,Topping Louise M,Stone Trevor W,Williams Richard O
Experimental gerontology
The IDO/kynurenine pathway is now established as a major regulator of immune system function. The initial enzyme, indoleamine 2,3-dioxygenase (IDO1) is induced by IFNγ, while tryptophan-2,3-dioxygenase (TDO) is induced by corticosteroids. The pathway is therefore positioned to mediate the effects of systemic inflammation or stress-induced steroids on tissue function and its expression increases with age. Disorders of the musculoskeletal system are a common feature of ageing and many of these conditions are characterized by an inflammatory state. In inflammatory arthritis and related disorders, kynurenine protects against the development of disease, while inhibition or deletion of IDO1 increases its severity. The long-term regulation of autoimmune disorders may be influenced by the epigenetic modulation of kynurenine pathway genes, with recent data suggesting that methylation of IDO may be involved. Osteoporosis is also associated with abnormalities of the kynurenine pathway, reflected in an inversion of the ratio between blood levels of the metabolites anthranilic acid and 3-hydroxy-anthranilic acid. This review discusses evidence to date on the role of the IDO/kynurenine pathway and the highly prevalent age-related disorders of osteoporosis and rheumatoid arthritis and identifies key areas that require further research.
10.1016/j.exger.2019.110820
[IL-6 up-regulates indoleamine 2, 3-dioxygenase (IDO) expression in chorionic villi and decidua].
Wang Rui,Weng Yuhong,Zhao Shuyun,Li Shixiang,Wen Xinghui,Huang Guanyou
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology
Objective To investigate the regulatory effect of interleukin-6 (IL-6) on the expression of indoleamine 2, 3-dioxygenase (IDO) in the early pregnant chorionic villi and decidua tissues. Methods The chorionic villi and decidua tissues of women who received induced abortion at early pregnancy were collected. The expression of IL-6 and IDO in the chorionic villi and decidua tissues was detected by Western blotting. Subsequently, 10, 50 and 100 ng/mL IL-6 was added into the chorionic villi and decidua tissues to culture for 48 hours. In addition, changes in the IDO mRNA and protein expression levels in chorionic villi and decidua tissues were detected by real-time quantitative reverse PCR (qRT-PCR) and Western blotting. Results Both IDO and IL-6 were expressed in human early pregnant chorionic villi and decidua tissues. Besides, the expression of these two proteins were positively correlated (r=0.72, 0.91). After being cultured with 10, 50 and 100 ng/mL IL-6 for 48 hours, IDO protein expression significantly increased in the cultured early pregnant chorionic villi and decidua tissues in an IL-6 concentration-dependent manner. Conclusion The expression of IL-6 and IDO proteins at the maternal-fetal interface show a positive correlation in normal physiological pregnancy, and IL-6 may up-regulate the expression of IDO.
Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation-Cancer Interface.
Cancers
The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.
10.3390/cancers15112895
Effects of indoleamine 2, 3-dioxygenase (IDO) silencing on immunomodulatory function and cancer-promoting characteristic of adipose-derived mesenchymal stem cells (ASCs).
Heidari Fahimeh,Razmkhah Mahboobeh,Razban Vahid,Erfani Nasrollah
Cell biology international
Indoleamine 2, 3-dioxygenase (IDO) catabolizes tryptophan, mediates immunomodulatory functions, and is released by stromal cells such as mesenchymal stem cells. The aims of this study were to investigate the effects of IDO silencing on immunosuppressive function of adipose-derived mesenchymal stem cells (ASCs), T cells phenotype, and the proliferation/migration of tumor cells. ASCs isolated from adipose tissues of healthy women were transfected with IDO-siRNA. Galectin-3, transforming growth factor-β1, hepatocyte growth factor, and interleukin-10 as immunomodulators were measured in ASCs using qRT-PCR. T cells phenotype, interferon-γ, and interleukin-17 expression were evaluated in peripheral blood lymphocytes (PBLs) cocultured with IDO silenced-ASCs by flow cytometry and qRT-PCR, respectively. Scratch assay was applied to assess the proliferation/migration of MDA-MB-231 cell line. Galectin-3 was upregulated (p ˂ 0.05) while hepatocyte growth factor was downregulated (p ˂ 0.05) in IDO-silenced ASCs compared to control groups. Regulatory T cells were inhibited in PBLs cocultured with IDO-silenced ASCs; also T helper2 was decreased in PBLs cocultured with IDO-silenced ASCs relative to the scramble group. IDO-silenced ASCs caused interferon-γ overexpression but interleukin-17 downregulation in PBLs. The proliferation/migration of MDA-MB-231 was suppressed after exposing to condition media of IDO-silenced ASCs compared with condition media of untransfected (p < 0.01) and scramble-transfected ASCs (p < 0.05). The results exhibited the weakened capacity of IDO-silenced ASCs for suppressing the immune cells and promoting the tumor cells' proliferation/migration. IDO suppression may be utilized as a strategy for cancer treatment. Simultaneous blocking of immunomodulators along with IDO inhibitors may show more effects on boosting the efficiency of immune-based cancer therapies.
10.1002/cbin.11698
The role of FoxP3+ regulatory T cells and IDO+ immune and tumor cells in malignant melanoma - an immunohistochemical study.
BMC cancer
BACKGROUND:FoxP3+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) participate in the formation of an immunosuppressive tumor microenvironment (TME) in malignant cutaneous melanoma (CM). Recent studies have reported that IDO expression correlates with poor prognosis and greater Breslow's depth, but results concerning the role of FoxP3+ Tregs in CM have been controversial. Furthermore, the correlation between IDO and Tregs has not been substantially studied in CM, although IDO is known to be an important regulator of Tregs activity. METHODS:We investigated the associations of FoxP3+ Tregs, IDO+ tumor cells and IDO+ stromal immune cells with tumor stage, prognostic factors and survival in CM. FoxP3 and IDO were immunohistochemically stained from 29 benign and 29 dysplastic nevi, 18 in situ -melanomas, 48 superficial and 62 deep melanomas and 67 lymph node metastases (LNMs) of CM. The number of FoxP3+ Tregs and IDO+ stromal immune cells, and the coverage and intensity of IDO+ tumor cells were analysed. RESULTS:The number of FoxP3+ Tregs and IDO+ stromal immune cells were significantly higher in malignant melanomas compared with benign lesions. The increased expression of IDO in melanoma cells was associated with poor prognostic factors, such as recurrence, nodular growth pattern and increased mitotic count. Furthermore, the expression of IDO in melanoma cells was associated with reduced recurrence-free survival. We further showed that there was a positive correlation between IDO+ tumor cells and FoxP3+ Tregs. CONCLUSIONS:These results indicate that IDO is strongly involved in melanoma progression. FoxP3+ Tregs also seems to contribute to the immunosuppressive TME in CM, but their significance in melanoma progression remains unclear. The positive association of FoxP3+ Tregs with IDO+ melanoma cells, but not with IDO+ stromal immune cells, indicates a complex interaction between IDO and Tregs in CM, which demands further studies.
10.1186/s12885-021-08385-4
IGFBP2 Drives Regulatory T Cell Differentiation through STAT3/IDO Signaling Pathway in Pancreatic Cancer.
Journal of personalized medicine
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies. Elevated regulatory T cell (Treg) infiltration has a potent immunosuppressive function in tumor biology, which contributes to low survival in PDAC. Nonetheless, the crosstalk between malignant cells and tumor-infiltrating Tregs in PDAC is not well understood. Here, clinical data demonstrates that the insulin-like growth factor binding protein 2 (IGFBP2) is associated with Treg accumulation in the microenvironment of PDAC in humans. Additionally, IGFBP2 increases Treg infiltration in the tumor microenvironment and promotes disease progression in mouse PDAC. Bioinformatic analysis and mechanistic assessment reveals IGFBP2 upregulated indoleamine 2, 3-dioxygenase (IDO) by activating signal transducer and activator of transcription 3 (STAT3) signaling in PDAC cells, thus inducing Treg differentiation and an immunosuppressive tumor microenvironment. These findings provide mechanistic insights into an important molecular pathway that promotes an immunosuppressive microenvironment, which suggests the IGFBP2 axis as a potential target for improved immune response in PDAC.
10.3390/jpm12122005
Effectiveness of Soluble CTLA-4-Fc in the Inhibition of Bone Marrow T-Cell Activation in Context of Indoleamine 2.3-Dioxygenase (IDO) and CD4Foxp3 Treg Induction.
Journal of inflammation research
Background:Rheumatoid arthritis (RA) is a chronic autoimmune disease with systemic inflammation finally resulting in damaged joints. One of the RA development models suggests bone marrow (BM) as a place of inflammation development further leading to disease progression. We aimed to investigate the potential of CTLA-4-Fc molecule in inducing tolerogenic milieu in BM measured as indoleamine 2,3-dioxygenase (IDO) expression, CD4Foxp3 Treg induction, and T cell activation control. The expression of IDO-pathway genes was also examined in monocytes to estimate the tolerogenic potential in the periphery. Methods:Bone marrow mononuclear cells (BMMC) were stimulated by pro-inflammatory cytokines and CTLA-4-Fc. Next IDO expression, CD4CD69 and CD4Foxp3 percentage were estimated by PCR and FACS staining, respectively. Enzymatic activity of IDO was confirmed by HPLC in BM plasma and blood plasma. Genes expressed in IDO-pathway were analyzed by NGS in peripheral monocytes isolated from RA patients and healthy controls. Results:We found that CTLA-4-Fc and IFN-γ stimulation results in IDO production by BMMC. CTLA-4-Fc induced tryptophan catabolism can inhibit mitogen-induced CD4 T cells activation without influencing CD8 cells, but did not control CD25 nor Foxp3 expression in BM cells. Significantly higher expression of selected IDO-pathway genes was detected on peripheral monocytes isolated from RA as compared to healthy controls. Conclusion:This study sheds light on some immunosuppression aspects present or induced in BM. The potential of IDO-mediated pathways were confirmed in the periphery, what may represent the promising candidates for therapeutic strategies in RA.
10.2147/JIR.S359775
Indoleamine 2,3 dioxygenase (IDO) level as a marker for significant coronary artery disease.
Wongpraparut Nattawut,Pengchata Ploy,Piyophirapong Sudarat,Panchavinnin Pariya,Pongakasira Rungtiwa,Arechep Noppadol,Kasetsinsombat Kanda,Maneechotesuwan Kittipong
BMC cardiovascular disorders
BACKGROUND:Indoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme in the kynurenine (Kyn) pathway of tryptophan (Trp) degradation, is modulated by inflammation, and is regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. Little is known about IDO activity in patients with active coronary artery disease (CAD). METHODS:We prospectively enrolled patients who were scheduled to undergo coronary angiography. Measurement of IDO, high-sensitivity troponin T (hs-TnT), and high-sensitivity C-reactive protein (hs-CRP) levels was performed at baseline, and IDO activity was monitored at the 6-month follow-up. RESULTS:Three hundred and five patients were enrolled. Ninety-eight patients (32.1%) presented with recent acute coronary syndrome (ACS). Significant difference in IDO, kynurenine, and hs-TnT between patients with and without significant CAD was observed. Baseline IDO activity, kynurenine level, and hs-TnT level were all significantly higher in significant CAD patients with 3-vessel, 2-vessel, and 1-vessel involvement than in those with insignificant CAD [(0.17, 0.13, and 0.16 vs. 0.03, respectively; p = 0.003), (5.89, 4.58, and 5.24 vs. 2.74 µM/g, respectively; p = 0.011), and (18.27, 12.22, and 12.86 vs. 10.89 mg/dL, respectively; p < 0.001)]. One-year mortality was 3.9%. When we compared between patients who survived and patients who died, we found a significantly lower prevalence of left main (LM) disease by coronary angiogram (6.1% vs. 33.3%, p = 0.007), and also a trend toward higher baseline kynurenine (5.07 vs. 0.79 µM/g, p = 0.082) and higher IDO (0.15 vs. 0.02, p = 0.081) in patients who survived. CONCLUSION:Immunometabolic response mediated via IDO function was enhanced in patients with CAD, and correlated with the extent and severity of disease. Patients with LM disease had higher 1-year mortality. Lower level of IDO, as suggested by inadequate IDO response, demonstrated a trend toward predicting 1-year mortality. Trial registration TCTR Trial registration number TCTR20200626001. Date of registration 26 June 2020. "Retrospectively registered".
10.1186/s12872-021-02140-0
Increased Indoleamine 2,3-Dioxygenase 1 (IDO-1) Activity and Inflammatory Responses during Chikungunya Virus Infection.
Pathogens (Basel, Switzerland)
Chikungunya virus (CHIKV) infection causes intense cytokine/chemokine inflammatory responses and debilitating joint pain. Indoleamine2,3-dioxygenase 1 (IDO-1) is an enzyme that initiates the tryptophan degradation that is important in initial host innate immune defense against infectious pathogens. Besides that, IDO-1 activation acts as a regulatory mechanism to prevent overactive host immune responses. In this study, we evaluated IDO-1 activity and cytokine/chemokine patterns in CHIKV patients. Higher IDO-1 (Kyn/Trp ratio) activation was observed during the early acute phase of CHIKV infection and declined in the chronic phase. Importantly, increased concentrations of Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Interferon γ (IFN-γ), C-C motif chemokine ligand 2/Monocyte Chemoattractant Protein-1 (CCL2/MCP-1) and C-X-C motif chemokine ligand 10/Interferon Protein-10 (CXCL10/IP-10) were found in the acute phase of infection, while C-C motif chemokine ligand 4/Macrophage Inflammatory Protein 1 β (CCL4/MIP-1β) was found at increased concentrations in the chronic phase. Likewise, CHIKV patients with arthritis had significantly higher concentrations of CCL4/MIP-1β compared to patients without arthritis. Taken together, these data demonstrated increased IDO-1 activity, possibly exerting both antiviral effects and regulating exacerbated inflammatory responses. CCL4/MIP-1β may have an important role in the persistent inflammation and arthritic symptoms following chikungunya infection.
10.3390/pathogens11040444
Characterizing the distributions of IDO-1 expressing macrophages/microglia in human and murine brains and evaluating the immunological and physiological roles of IDO-1 in RAW264.7/BV-2 cells.
Ji Rong,Ma Lixiang,Chen Xinyu,Sun Renqiang,Zhang Li,Saiyin Hexige,Wei Wenshi
PloS one
Indoleamine 2,3-dioxygenase 1 (IDO-1) is an immunosuppressive enzyme expressed in the placenta, neoplastic cells, and macrophages to reject T cells by converting tryptophan into kynurenine. However, the role of IDO-1 in brain immunity, especially in the meninges, is unclear. We aim to elucidate the distribution pattern of IDO-1+ macrophages/microglia in the human brain tissues, human glioblastoma, APP/PS1 mouse brains, and quinolinic acid model brains and explore the physiological and immunological roles of IDO-1+ macrophages/microglia. Here, we find that both human and mouse macrophages/microglia of the perivascular and subarachnoid space and in glioblastoma (GBM) expressed IDO-1 but not macrophages/microglia of parenchyma. Using IDO-1 inhibitors including 1-MT and INCB24360, we observed that inhibiting IDO-1 reduced the cellular size and filopodia growth, fluid uptake, and the macropinocytic and phagocytic abilities of human blood monocytes and RAW264.7/BV-2 cells. Inhibiting IDO-1 with 1-MT or INCB24360 increased IL-1β secretion and suppressed NLRP3 expression in RAW264.7/BV-2 cells. Our data collectively show that IDO-1 expression in perivascular and meninges macrophages/microglia increases cellular phagocytic capacity and might suppress overactivation of inflammatory reaction.
10.1371/journal.pone.0258204
PD-1, PD-L1, IDO, CD70 and microsatellite instability as potential targets to prevent immune evasion in sarcomas.
Immunotherapy
Soft tissue and bone sarcomas are rare entities, hence, standardized therapeutic strategies are difficult to assess. Immunohistochemistry was performed on 68 sarcoma samples to assess the expression of PD-1, PD-L1, IDO and CD70 in different tumor compartments and molecular analysis was performed to assess microsatellite instability status. PD-1/PD-L1, IDO and CD70 pathways are at play in the immune evasion of sarcomas in general. Soft tissue sarcomas more often show an inflamed phenotype compared with bone sarcomas. Specific histologic sarcoma types show high expression levels of different markers. Finally, this is the first presentation of a microsatellite instability-high Kaposi sarcoma. Immune evasion occurs in sarcomas. Specific histologic types might benefit from immunotherapy, for which further investigation is needed.
10.2217/imt-2022-0049
Fatigue in Patients on Chronic Hemodialysis: The Role of Indoleamine 2,3-Dioxygenase (IDO) Activity, Interleukin-6, and Muscularity.
Nutrients
Fatigue is a frequent symptom in hemodialysis (HD), and the indolamine-2,3-dioxygenase (IDO) metabolic trap has been hypothesized in the pathogenesis of fatigue. The association between IDO activity according to fatigue and its relationship with muscle mass and function in HD patients was verified. Chronic HD patients were considered, and fatigue was assessed. The plasma kynurenines and tryptophan ratio (Kyn/Trp), as surrogate of IDO activity, and interleukin (IL)-6 were measured. Muscularity was assessed by BIA and muscle strength by hand-grip dynamometer. 50 HD patients were enrolled, and fatigue was present in 24% of the cohort. Patients with fatigue showed higher Kyn/Trp ( = 0.005), were older ( = 0.007), and IL-6 levels resulted higher than in non-fatigue patients ( < 0.001). HD patients with fatigue showed lower intracellular water (surrogate of muscle mass) ( < 0.001), as well as lower hand grip strength ( = 0.02). The Kyn/Trp ratio positively correlated with IL-6 and ECW/ICW ( = 0.004 and = 0.014). By logistic regression analysis, higher ICW/h was associated with lower odds of fatigue (OR, 0.10; 95% CI, 0.01 to 0.73). In conclusion, our cohort fatigue was associated with a higher Kyn/Trp ratio, indicating a modulation of IDO activity. The Kyn/Trp ratio correlated with IL-6, suggesting a potential role of IDO and inflammation in inducing fatigue and changes in muscularity.
10.3390/nu15040876
Gain‑of‑function of IDO in DCs inhibits T cell immunity by metabolically regulating surface molecules and cytokines.
Experimental and therapeutic medicine
Both tolerogenicity and immunogenicity of dendritic cells (DCs) are regulated by their intracellular metabolism. As a rate-limiting enzyme of tryptophan (Trp) metabolism, indoleamine 2,3-dioxygenase (IDO) is involved in regulating the functions of numerous cell types, including DCs, a subset of which has a high capacity for producing IDO to control over-activated inflammation. To identify the mechanisms of IDO in DCs, stable DC lines with both gain- and reduction-of-function of IDO were established using a recombinant DNA technique. Although the IDO variation did not affect DC survival and migration, it altered Trp metabolism and other features of DCs analyzed by high-performance liquid chromatography and flow cytometry. On the surface of the DCs, IDO inhibited co-stimulatory CD86 but promoted co-inhibitory programmed cell death ligand 1 expression, and suppressed the antigen uptake, which ultimately led to the compromised ability of DCs to activate T cells. Furthermore, IDO also suppressed IL-12 secretion but enhanced that of IL-10 in DCs, which eventually induced T cells into tolerogenic phenotypes by inhibiting the differentiation of Th1 but promoting that of regulatory T cells. Collectively, the findings of the present study demonstrated that IDO is a key molecule for tolerogenic DC induction by metabolically regulating surface molecule and cytokine expression. This conclusion may lead to the targeted development of therapeutic drugs for autoimmune diseases.
10.3892/etm.2023.11933
PD-L1 is Fascinating but IDO Needs Attention in Non-HCV and Non-HBV-Associated Hepatocellular Carcinoma Patients.
Journal of hepatocellular carcinoma
Background/Aim:Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer that is modulated by the immune system. Programmed cell death ligand-1 (PD-L1) has emerged as a novel therapeutic target in various cancers. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that is associated with poor prognoses in various cancer types. The aim of this study was to investigate the PD-L1 expression, and clinicopathological features of non-HCV and non-HBV-associated HCC patients, including IDO expression. Patients and Methods:In this study, immunohistochemical analysis was performed to analyze the expression of PD-L1 and IDO. Formalin-fixed paraffin-embedded HCC tumor tissues (n=50) were obtained from the pathology department, at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC) in Lahore, Pakistan between 2005 and 2022. All the patients were HBV and HCV negative. Furthermore, it was a rare group of patients with no previous history of any viral hepatitis. In addition, for categorical and continuous variables chi-square or Fisher exact test and Mann-Whitney -test was performed. Results:Of 50 tissue specimens, PD-L1+ was observed in 21 [high: 12 (24%), low: 9 (18%)] and PD-L1- was observed in 29 HCC patients. IDO+ was observed in all 50 specimens [high: 42 (84%), low: 8 (16%)]. Additionally, both PD-L1 and IDO had high expression in 11 (22%) patients. While both PD-L1 and IDO had low expression in 2 (4%) patients. Furthermore, in IDO+/PD-L1- group, 20 (69%) out of 29 patients died while in the IDO+/PD-L1+ group, 9 (43%) out of 21 patients died. Conclusion:Evaluation of IDO and PD-L1 expression may add therapeutic advantage in non-HCV and non-HBV-associated HCC patients that overexpress IDO. Further validation in a larger cohort is warranted.
10.2147/JHC.S409741
Indoleamine 2,3-Dioxygenase (IDO) Activity: A Perspective Biomarker for Laboratory Determination in Tumor Immunotherapy.
Biomedicines
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme involved in catalyzing the conversion of tryptophan (Trp) into kynurenine (Kyn) at the first rate-limiting step in the kynurenine pathway of L-tryptophan metabolism. It has been found to be involved in several biological functions such as aging, immune microorganism, neurodegenerative and infectious diseases, and cancer. IDO1 plays an important role in immune tolerance by depleting tryptophan in the tumor microenvironment and inhibiting the proliferation of effector T cells, which makes it an important emerging biomarker for cancer immunotherapy. Therefore, the research and development of IDO1 inhibitors are of great importance for tumor therapy. Of interest, IDO activity assays are of great value in the screening and evaluation of inhibitors. Herein, we mainly review the biological functions of IDO1, immune regulation, key signaling molecules in the response pathway, and the development of IDO1 inhibitors in clinical trials. Furthermore, this review provides a comprehensive overview and, in particular, a discussion of currently available IDO activity assays for use in the evaluation of IDO inhibitors in human blood. We believe that the IDO activity is a promising biomarker for the immune escape and laboratory evaluation of tumor immunotherapy.
10.3390/biomedicines11071988
IDO blockade negatively regulates the CTLA-4 signaling in breast cancer cells.
Immunologic research
Cancer is classified into metabolic and/or genetic disorders; notably, the tryptophan catabolism pathway is vital in different cancer types. Here, we focused on the interaction and molecular connection between the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptor and indoleamine-2,3-dioxygenase (IDO) enzyme. To test the impact of the selected immunotherapies on breast cancer cell migration and cell survival, we used in vitro assays. Also, we test the impact of anti-CTLA-4 antibody on the IDO-positive cells. The results of cell migration and clonogenic assays showed that anti-CTLA-4 antibody reduces cancer cell migration and clonogenic abilities of murine breast cancer cells. In addition, the result of flow cytometry showed that the anti-CTLA-4 antibody did not change the percentage of IDO-positive cancer cells. Notably, administrating an IDO blocker, 1-Methyl-DL-tryptophan (1MT), reduces the efficiency of the antiCTLA-4 antibody. The enzymatic blocking of the IDO reduces the efficiency of the anti-CTLA-4 antibody on cell migration and clonogenic abilities suggesting that there is an inhibitory interaction at the molecular level between functions of CTLA-4 and IDO. It is unclear via which mechanism(s) IDO interacts with CTLA-4 signaling and also why blocking IDO makes disruption in CTLA-4 signaling in cancer cells. Indeed, evaluating the role of IDO in CTLA-4 signaling in cancer cells may assist in clarifying a poor response to CTLA-4 immunotherapies by some patients. Hence, further investigation of the molecular interaction between CTLA-4 and IDO might help to improve the efficiency of CTLA-4 immunotherapy.
10.1007/s12026-023-09378-0
IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.
The International journal of neuroscience
AIM:Postoperative cognitive dysfunction (POCD) is a common postoperative complication, especially in elderly patients. It extends hospital stay, increases the mortality rate and are heavy burdens to the family and society. Accumulating research has indicated that overactivation of pyrin domain-containing protein 3 (NLRP3) inflammasomes is related to POCD andplays a critical role in activating pro-inflammatory cytokines. According to existing studies, indoleamine 2,3-dioxygenase (IDO) is potently up-regulated by inflammatory factors, tryptophan in brain is mainly catalyzed by IDO to kynurenine (KYN), KYN metabolism may contribute to the development of depressive disorder and memory deficits. Hence, this study elucidated whether IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice. MATERIAL AND METHODS:POCD model was established in aged C57BL/6J mice by exploratory laparotomy under isoflurane anesthesia. Learning and memory were determined using Morris water maze. RESULTS:The data showed that IDO and kynurenine aminotransferase-II (KAT-II) mRNA in hippocampus was up-regulated, and NLRP3, caspase recruitment domain (ASC), interleukin-1b (IL-1b) and IDO overexpressed, KYN levels increased after anesthesia and surgery. NLRP3 inflammasome inhibitor (MCC950) reversed NLRP3, ASC, IL-1b and IDO overexpression, and the elevation of KYN levels. To clarify the role of IDO-Kynurenine pathway in postoperative cognitive impairment, IDO inhibitor (1-methyl-Ltryptophan 1-MT) reduced the elevation of KYN and kynurenic acid (KYNA) levels, reduction of tryptophan (TRP), as well as improved learning and memory abilities. Finally, KAT-II inhibitor (PF-04859989) reduced brain KYNA levels and restored the cognitive impairment. CONCLUSION:These results reveal that IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment.
10.1080/00207454.2023.2262741
Alleviation of Rheumatoid Arthritis by Inducing IDO Expression with Recombinant Protein 43.
Journal of immunology research
Rheumatoid arthritis (RA) represents the autoimmune disorder that shows aggressive arthritis as the main symptom. It is difficult to treat and can lead to joint deformation and function loss. At present, () antigen has attracted much attention because it plays a role in host immune regulatory mechanisms. Therefore, we selected recombinant protein 43 (Tsp43) to treat the bovine collagen type II (BCII)-induced mice RA model and explored its therapeutic mechanisms. This work first verified that Tsp43 could promote the expression of indoleamine 2, 3-dioxygenase (IDO) in dendritic cells (DCs) in vitro. Then, we randomized BALB/c mice (8 weeks old) into six groups, including control, phosphate buffer saline (PBS), BCII, BCII + heat inactivated Tsp43 (HiTsp43), BCII + Tsp43, and BCII + Tsp43 + 1-methyl-troptophan (1-MT) groups. To determine the therapeutic effect of Tsp43 on the BCII-induced mice RA model, relevant cytokines in each group and pathological changes in ankle joints were detected. To explore the mechanisms of Tsp43 on the BCII-induced mice RA model, we checked the expression of IDO in each group, CD4T cell proliferation, and apoptosis. Collectively, Tsp43 decreased tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) expression in BCII-induced mice RA model and recovered the ankle injury to a certain extent. Tsp43 promoted high expression of IDO, caused expression of related apoptotic proteins in CD4T cells, and caused apoptosis in CD4T cells. In addition, Tsp43 reduced the proliferation of CD4T cells. However, these effects can be inhibited by 1-MT (IDO inhibitor). These results suggested that Tsp43 played an important role in the treatment of arthritis by inhibiting the proliferation of CD4T cells and inducing CD4T cells apoptosis through the high expression of IDO. The purpose of this experiment was to provide a new idea for the treatment of RA and lay a foundation for the development of parasite-derived drugs for the treatment of RA.
10.1155/2024/8816919
IDO/Kynurenine; novel insight for treatment of inflammatory diseases.
Cytokine
Inflammation and oxidative stress play pivotal roles in pathogenesis of many diseases including cancer, type 2 diabetes, cardiovascular disease, atherosclerosis, neurological diseases, and inflammatory diseases such as inflammatory bowel disease (IBD). Inflammatory mediators such as interleukins (ILs), interferons (INF-s), and tumor necrosis factor (TNF)-α are related to an extended chance of inflammatory diseases initiation or progression due to the over expression of the nuclear factor Kappa B (NF-κB), signal transducer of activators of transcription (STAT), nod-like receptor family protein 3 (NLRP), toll-like receptors (TLR), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) pathways. These pathways are completely interconnected. Theindoleamine 2,3 dioxygenase (IDO) subset of the kynurenine (KYN) (IDO/KYN), is a metabolic inflammatory pathway involved in production of nicotinamide adenine dinucleotide (NAD + ). It has been shown that IDO/KYN actively participates in inflammatory processes and can increase the secretion of cytokines that provoke inflammatory diseases. Data were extracted from clinical and animal studies published in English between 1990-April 2022, which were collected from PubMed, Google Scholar, Scopus, and Cochrane library. IDO/KYN is completely associated with inflammatory-related pathways, thus leading to the production of cytokines such as TNF-α, IL-1β, and IL-6, and ultimately development and progression of various inflammatory disorders. Inhibition of the IDO/KYN pathway might be a novel therapeutic option for inflammatory diseases. Herein, we gathered data on probable interactions of the IDO/KYN pathway with induction of some inflammatory diseases.
10.1016/j.cyto.2023.156206
A theoretical study on the activity and selectivity of IDO/TDO inhibitors.
Physical chemistry chemical physics : PCCP
Indoleamine 2,3-dioxygenase 1 (IDO) is a tryptophan (Trp) metabolic enzyme along the kynurenine (NFK) pathway. Under pathological conditions, IDO overexpressed by tumor cells causes depletion of tryptophan and the accumulation of metabolic products, which inhibit the local immune response and form immune escape. Therefore, the suppression of IDO activity is one of the strategies for tumor immunotherapy, and drug design for this target has been the focus of research for more than two decades. Apart from IDO, tryptophan dioxygenase (TDO) of the same family can also catalyze the same biochemical reaction in the human body, but it has different tissue distribution and substrate selectivity from IDO. Based on the principle of drug design with high potency and low cross-reactivity to specific targets, in this subject, the activity and selectivity of IDO and TDO toward small molecular inhibitors were studied from the perspective of thermodynamics and kinetics. The aim was to elucidate the structural requirements for achieving favorable biological activity and selectivity of IDO and TDO inhibitors. Specifically, the interactions of inhibitors from eight families with IDO and TDO were initially investigated through molecular docking and molecular dynamics simulations, and the thermodynamic data for binding of inhibitors were predicted by the molecular mechanics/generalized Born surface area (MM/GBSA) method. Secondly, we explored the free energy landscape of JKloops, the kinetic control element of IDO/TDO, using temperature replica exchange molecular dynamics (T-REMD) simulations and elucidated the connection between the rules of IDO/TDO conformational changes and the inhibitor selectivity mechanism. Furthermore, the binding and dissociation processes of the C1 inhibitor (NLG919) were simulated by the adaptive steering molecular dynamics (ASMD) method, which not only addressed the possible stable, metastable, and transition states for C1 inhibitor-IDO/TDO interactions, but also accurately predicted kinetic data for C1 inhibitor binding and dissociation. In conclusion, we have constructed a complete process from enzyme (IDO/TDO) conformational activation to inhibitor binding/dissociation and used the thermodynamic and kinetic data of each link as clues to verify the control mechanism of IDO/TDO on inhibitor selectivity. This is of great significance for us to understand the design principles of tumor immunotherapy drugs and to avoid drug resistance of immunotherapy drugs.
10.1039/d3cp06036e
Dendritic cell-expressed IDO alleviates atherosclerosis by expanding CD4CD25Foxp3Tregs through IDO-Kyn-AHR axis.
International immunopharmacology
Atherosclerosis is a chronic inflammatory disease, in which immune disorders constitute an essential part of vascular pathogenesis. Accumulating evidence indicates that dendritic cells (DCs) and their tryptophan metabolisms regulate host immune responses. However, the mechanistic involvement of metabolic products from DCs in dysregulating vascular immunity during the development of atherosclerosis is far from clear. Flow cytometry examination showed immune cells were accumulated and gradually increased in the atherosclerotic lesions during the atherosclerosis progression, in which IDODCs were enriched. To study the role of DC-expressed IDO in the development of atherosclerosis, we made a stable IDO-overexpressing DC line (IDODCs) by lentiviral infection for adoptive transfer into pro-atherosclerotic mice. Compared with DCs containing empty vector (VectorDC)-treated group, treatment of IDODCs led to a significant reduction of atherosclerotic lesions in the aorta, with decreased aortic infiltration of Th1 immune cells and reduced vascular inflammation. Importantly, IDODCs increased aortic kynurenine (Kyn) concentration and aryl hydrocarbon receptor (AHR) expression, concomitant with CD4CD25Foxp3Treg expansion in the aortic tissues, which were abrogated by AHR antagonist treatment. These results indicate that DC-expressed IDO reduces atherosclerotic lesions by inducing aortic CD4CD25Foxp3Treg expansion through IDO-Kyn-AHR axis, which may represent a novel possibility for treatment or prevention of atherosclerosis.
10.1016/j.intimp.2023.109758