Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Nov 3;18(21):11545.
doi: 10.3390/ijerph182111545.

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

Michelle Broekhuizen  1   2   3 , A H Jan Danser  1 , Irwin K M Reiss  2 , Daphne Merkus  3   4
Affiliations
Review

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

Michelle Broekhuizen et al. Int J Environ Res Public Health. .

Abstract

(L-)tryptophan is metabolized via the kynurenine pathway into several kynurenine metabolites with distinct functions. Dysfunction of the kynurenine pathway can lead to impairments in vascular regulation, immune regulation, and tolerance. The first and rate limiting enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is highly expressed in the placenta and reduced in placentas from complicated pregnancies. IDO is essential during pregnancy, as IDO inhibition in pregnant mice resulted in fetal loss. However, the exact function of placental IDO, as well as its exact placental localization, remain controversial. This review identified that two isoforms of IDO; IDO1 and IDO2, are differently expressed between placental cells, suggesting spatial segregation. Furthermore, this review summarizes how the placental kynurenine pathway is altered in pregnancy complications, including recurrent miscarriage, preterm birth, preeclampsia, and fetal growth restriction. Importantly, we describe that these alterations do not affect maternally circulating metabolite concentrations, suggesting that the kynurenine pathway functions as a local signaling pathway. In the placenta, it is an important source of de novo placental NAD+ synthesis and regulates fetal tryptophan and kynurenine metabolite supply. Therefore, kynurenine pathway interventions might provide opportunities to treat pregnancy complications, and this review discusses how such treatment could affect placental function and pregnancy development.

Keywords: indoleamine 2,3-dioxygenase; kynurenine; placenta; pregnancy; therapy; tryptophan.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of a term placenta with its most abundant cell types. CTB, cytotrophoblast; EC, endothelial cell; EVT, extravillous trophoblast; Fib, fibroblast; HB, Hofbauer cell; Mac, macrophage; STB, syncytiotrophoblast.
Figure 2
Figure 2
The kynurenine pathway. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygense; AFMID, arylformamidase; KAT-2, aminoadipate aminotransferase; KAT-3, kynurenine aminotransferase 3; KYNU, kynureninase; KMO, kynurenine 3-monooxygenase; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; ACMSD, aminocarboxymuconate semialdehyde decarboxylase; QPRT, quinolinate phosphoribosyltransferase.
Figure 3
Figure 3
Cell type specific mRNA expression of kynurenine pathway enzymes, receptor, and transporters in placental tissue. Data were obtained using the single cell RNA sequencing data from first trimester placentas by Vento-Tormo et al. [49] (A), and term placentas by Pique-Regi et al. [50] (B) and Tsang et al. [51] (C). The cell types are clustered based on immune cells (blue) or non-immune cells (yellow). The size of the symbols reflects the number of cells within a certain cell type expressing the gene, whereas the color of the symbol reflects the relative expression of each gene. NK, natural killer; npi, non-proliferating interstitial; IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygense; AFMID, arylformamidase; KAT2, aminoadipate aminotransferase; KAT3, kynurenine aminotransferase 3; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; QPRT, quinolinate phosphoribosyltransferase; ACMSD, aminocarboxymuconate semialdehyde decarboxylase.
Figure 4
Figure 4
Illustration of kynurenine pathway enzymes and transporters localization in the first trimester and term placenta. This figure only shows the expression of enzymes (red) and transporters (yellow) confirmed by single cell RNA sequencing and/or immunohistochemistry data. The directions and interactions are a hypothetical display of the placental kynurenine pathway. How kynurenine pathway metabolites are exchanged between these cells, and whether this is facilitated by these, or other yet unidentified transporters is currently unknown. Enzymes (red): IDO, indoleamine 2,3-dioxygenase; KYNU, kynureninase; KMO, kynurenine 3-monooxygenase; QPRT, quinolinate phosphoribosyltransferase. Potential transporters (yellow): large neutral amino acid transporter (LAT); LAT1/2 depicts both LAT1 and LAT2 can be involved. Kynurenine pathway metabolites (green): Trp, L-tryptophan; Kyn, L-kynurenine; 3-HKyn, 3-hydroxykynurenine; 3-HAA, 3-hydroxyanthranilic acid; Quin, quinolinic acid; NAD+, nicotinamide adenine dinucleotide. Placental cell types in grey: CTB, cytotrophoblast; EC, endothelial cell; EVT, extravillous trophoblast; Fib, fibroblast; HB, Hofbauer cell; Mac, macrophage; STB, syncytiotrophoblast.
Figure 5
Figure 5
The kynurenine pathway with pharmacological interventions. L-Leucine is a natural competitor for Tryptophan transport by LAT1. The lipid soluble form of tryptophan, tryptophan ethyl ester, can circumvent the amino acid transporters. Epacadostat selectively inhibits IDO1. JM6 is an inhibitor of KMO. AV-101 (4-chlorokynurenine) is a prodrug of 4-chloro-3-hydroxyanthranilic acid, a potent inhibitor of HAAO. NAC (N-acetylcysteine) inhibits KAT2, and the subsequent formation of kynurenic acid and potentially xanthurenic acid. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygense; AFMID, arylformamidase; KAT-2, aminoadipate aminotransferase; KAT-3, kynurenine aminotransferase 3; KYNU, kynureninase; KMO, kynurenine 3-monooxygenase; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; ACMSD, aminocarboxymuconate semialdehyde decarboxylase; QPRT, quinolinate phosphoribosyltransferase; LAT, large neutral amino acid transporter.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Peters J.C. Tryptophan nutrition and metabolism: An overview. Adv. Exp. Med. Biol. 1991;294:345–358. doi: 10.1007/978-1-4684-5952-4_32. - DOI - PubMed
    1. Ball H.J., Sanchez-Perez A., Weiser S., Austin C.J., Astelbauer F., Miu J., McQuillan J.A., Stocker R., Jermiin L.S., Hunt N.H. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene. 2007;396:203–213. doi: 10.1016/j.gene.2007.04.010. - DOI - PubMed
    1. Metz R., Duhadaway J.B., Kamasani U., Laury-Kleintop L., Muller A.J., Prendergast G.C. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007;67:7082–7087. doi: 10.1158/0008-5472.CAN-07-1872. - DOI - PubMed
    1. Boyland E., Williams D.C. The metabolism of tryptophan. 2. The metabolism of tryptophan in patients suffering from cancer of the bladder. Biochem. J. 1956;64:578–582. doi: 10.1042/bj0640578. - DOI - PMC - PubMed
    1. Prendergast G.C., Malachowski W.P., DuHadaway J.B., Muller A.J. Discovery of IDO1 Inhibitors: From Bench to Bedside. Cancer Res. 2017;77:6795–6811. doi: 10.1158/0008-5472.CAN-17-2285. - DOI - PMC - PubMed