Tryptophan metabolism and immune regulation in the human placenta

Silvano, Angela; Seravalli, Viola; Strambi, Noemi; Cecchi, Matteo; Tartarotti, Enrico; Parenti, Astrid; Tommaso, Mariarosaria Di

doi:10.1016/j.jri.2021.103361

Cited by 25 publications

(32 citation statements)

References 120 publications

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“…As mentioned previously, tryptophan is an essential amino acid that is involved in maintaining the immune privilege of the placenta 116 through the kynurenine pathway that is catalyzed by IDO. 117 After pregnancy, IDO-mediated tryptophan degradation in decidual and peripheral leukocytes was activated coupled with elevated kynurenine. 118 Further analysis showed that IFNγ or cytotoxic T lymphocyte antigen-4 stimulation could increase the expression of IDO in dMφ.…”

Section: Amino Acid Metabolismmentioning

confidence: 99%

The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss*

Zhang

Shen

Qin

et al. 2022

Immunological Reviews

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Maternal tolerance to semi‐ or fully allograft conceptus is a prerequisite for the maintenance of pregnancy. Once this homeostasis is disrupted, it may result in pregnancy loss. As a potential approach to prevent pregnancy loss, targeting decidual immune cells (DICs) at the maternal‐fetal interface has been suggested. Although the phenotypic features and functions of DIC have been extensively profiled, the regulatory pathways for this unique immunological adaption have yet to be elucidated. In recent years, a pivotal mechanism has been highlighted in the area of immunometabolism, by which the changes in intracellular metabolic pathways in DIC and interaction with the adjacent metabolites in the microenvironment can alter their phenotypes and function. More inspiringly, the manipulation of metabolic profiling in DIC provides a novel avenue for the prevention and treatment of pregnancy loss. Herein, this review highlights the major metabolic programs (specifically, glycolysis, ATP‐adenosine metabolism, lysophosphatidic acid metabolism, and amino acid metabolism) in multiple immune cells (including decidual NK cells, macrophages, and T cells) and their integrations with the metabolic microenvironment in normal pregnancy. Importantly, this perspective may help to provide a potential therapeutic strategy for reducing pregnancy loss via targeting this interplay.

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Section: Amino Acid Metabolismmentioning

confidence: 99%

The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss*

Zhang

Shen

Qin

et al. 2022

Immunological Reviews

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show abstract

“…performed a pioneering experiment showing that elevated IDO (namely, IDO1) expression at the maternal–fetal interface was crucial to prevent immune rejection of fetal allografts ( 11 ). Subsequently, extensive studies have demonstrated the immunological regulation role for IDO1 in physiological and pathological states including pregnancy, obesity, transplantation, infectious diseases, autoimmune diseases, neurological diseases, and neoplastic diseases ( 69 – 72 ). In clinical researches, the expression of IDO1 has been found in various tumors such as breast cancer, melanoma, and bladder cancer, which inactivates surrounding immune cells in TME primarily through abnormalities of Trp metabolism ( 54 , 73 , 74 ).…”

Section: Indoleamine 23-dioxygenase 1 In Modulating the Immunosuppressive Tumor Microenvironmentmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase 1: A Promising Therapeutic Target in Malignant Tumor

Song

et al. 2021

Front. Immunol.

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Tumorigenesis is a complex multifactorial and multistep process in which tumors can utilize a diverse repertoire of immunosuppressive mechanisms to evade host immune attacks. The degradation of tryptophan into immunosuppressive kynurenine is considered an important immunosuppressive mechanism in the tumor microenvironment. There are three enzymes, namely, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2), involved in the metabolism of tryptophan. IDO1 has a wider distribution and higher activity in catalyzing tryptophan than the other two; therefore, it has been studied most extensively. IDO1 is a cytosolic monomeric, heme-containing enzyme, which is now considered an authentic immune regulator and represents one of the promising drug targets for tumor immunotherapy. Collectively, this review highlights the regulation of IDO1 gene expression and the ambivalent mechanisms of IDO1 on the antitumoral immune response. Further, new therapeutic targets via the regulation of IDO1 are discussed. A comprehensive analysis of the expression and biological function of IDO1 can help us to understand the therapeutic strategies of the inhibitors targeting IDO1 in malignant tumors.

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“…In addition to its role in protein synthesis, L-Trp is a precursor for two important metabolic pathways, the kynurenine pathway (KP), and the serotonin pathway ( Richard et al, 2009 ; Barik, 2020 ). Physiologically, L-Trp and its metabolites are key regulators of energy production, cellular redox state, neuronal and vascular function, wound healing, as well as innate and adaptive immunity ( Richard et al, 2009 ; Serbecic et al, 2009 ; Li et al, 2012 ; Boccuto et al, 2013 ; Barik, 2020 ; Costantini et al, 2020 ; Fiore and Murray, 2021 ; Haq et al, 2021 ; Silvano et al, 2021 ). Importantly, induction of L-Trp metabolic pathways not only facilitates immunological tolerance and maintenance of immune privilege in the eyes, brain, and placenta, but also modulates pathogen replication through regulation of L-Trp bioavailability ( Serbecic et al, 2009 ; Li et al, 2012 ; Costantini et al, 2020 ; Fiore and Murray, 2021 ; Silvano et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Physiologically, L-Trp and its metabolites are key regulators of energy production, cellular redox state, neuronal and vascular function, wound healing, as well as innate and adaptive immunity ( Richard et al, 2009 ; Serbecic et al, 2009 ; Li et al, 2012 ; Boccuto et al, 2013 ; Barik, 2020 ; Costantini et al, 2020 ; Fiore and Murray, 2021 ; Haq et al, 2021 ; Silvano et al, 2021 ). Importantly, induction of L-Trp metabolic pathways not only facilitates immunological tolerance and maintenance of immune privilege in the eyes, brain, and placenta, but also modulates pathogen replication through regulation of L-Trp bioavailability ( Serbecic et al, 2009 ; Li et al, 2012 ; Costantini et al, 2020 ; Fiore and Murray, 2021 ; Silvano et al, 2021 ). Indeed, one mechanism by which interferon gamma (IFN-g) suppresses pathogen replication, including Chlamydia, Hepatitis B virus, and Parainfluenza virus, is by depleting L-Trp through activation of indoleamine-pyrrole 2,3-dioxygenase (IDO) and the initial KP rate-limiting enzyme ( Carlin et al, 1989 ; Lepiller et al, 2015 ; Rabbani et al, 2016 ; Yoshio et al, 2016 ; Raniga and Liang, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease

et al. 2022

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Herpes simplex virus-associated diseases are a complex interaction between cytolytic viral replication and inflammation. Within the normally avascular and immunoprivileged cornea, HSV ocular infection can result in vision-threatening immune-mediated herpetic keratitis, the leading infectious cause of corneal blindness in the industrialized world. Viral replicative processes are entirely dependent upon numerous cellular biosynthetic and metabolic pathways. Consistent with this premise, HSV infection was shown to profoundly alter gene expression associated with cellular amino acid biosynthetic pathways, including key tryptophan metabolism genes. The essential amino acid tryptophan is crucial for pathogen replication, the generation of host immune responses, and the synthesis of neurotransmitters, such as serotonin. Intriguingly, Tryptophan hydroxylase 2 (TPH2), the neuronal specific rate-limiting enzyme for serotonin synthesis, was the most significantly upregulated gene by HSV in an amino acid metabolism PCR array. Despite the well-defined effects of serotonin in the nervous system, the association of peripheral serotonin in disease-promoting inflammation has only recently begun to be elucidated. Likewise, the impact of serotonin on viral replication and ocular disease is also largely unknown. We therefore examined the effect of HSV-induced serotonin-associated synthesis and transport pathways on HSV-1 replication, as well as the correlation between HSV-induced ocular serotonin levels and disease severity. HSV infection induced expression of the critical serotonin synthesis enzymes TPH-1, TPH-2, and DOPA decarboxylase (DDC), as well as the serotonin transporter, SERT. Concordantly, HSV-infected cells upregulated serotonin synthesis and its intracellular uptake. Increased serotonin synthesis and uptake was shown to influence HSV replication. Exogenous addition of serotonin increased HSV-1 yield, while both TPH-1/2 and SERT pharmacological inhibition reduced viral yield. Congruent with these in vitro findings, rabbits intraocularly infected with HSV-1 exhibited significantly higher aqueous humor serotonin concentrations that positively and strongly correlated with viral load and ocular disease severity. Collectively, our findings indicate that HSV-1 promotes serotonin synthesis and cellular uptake to facilitate viral replication and consequently, serotonin’s proinflammatory effects may enhance the development of ocular disease.

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Tryptophan metabolism and immune regulation in the human placenta

Cited by 25 publications

References 120 publications

The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss*

The metabolic characteristic of decidual immune cells and their unique properties in pregnancy loss*

Indoleamine 2,3-Dioxygenase 1: A Promising Therapeutic Target in Malignant Tumor

Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease

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