Tryptophan 2,3-Dioxygenase Expression Identified in Murine Decidual Stromal Cells Is Not Essential for Feto-Maternal Tolerance

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the rate-limiting step of tryptophan catabolism along the kynurenine pathway, which has important immuno suppressive properties, particularly in tumor cells and dendritic cells. The prominent expression of IDO1 in the placenta also suggested a role in preventing immune rejection of fetal tissues, and pharmacological inhibition of IDO1 induced abortion of allogeneic fetuses in mice. However, this was later challenged by the lack of rejection of allogeneic fetuses in IDO1-KO mice, suggesting that other mechanisms may compensate for IDO1 deficiency. Here we investigated whether TDO could contribute to feto-maternal tolerance and compensate for IDO1 deficiency in IDO1-KO mice. Expression of TDO mRNA was previously detected in placental tissues. We developed a new chimeric rabbit anti-TDO antibody to confirm TDO expression at the protein level and identify the positive cell type by immunohistochemistry in murine placenta. We observed massive TDO expression in decidual stromal cells, starting at day E3.5, peaking at day E6.5 then declining rapidly while remaining detectable until gestation end. IDO1 was also induced in decidual stromal cells, but only at a later stage of gestation when TDO expression declined. To determine whether TDO contributed to feto-maternal tolerance, we mated TDO-KO and double IDO1-TDO-KO females with allogeneic males. However, we did not observe reduced fertility. These results suggest that, despite its expression in decidual stromal cells, TDO is not a dominant mechanism of feto-maternal tolerance able to compensate for the absence of IDO1. Redundant additional mechanisms of immunosuppression likely take over in these KO mice. The massive expression of TDO during decidualization might suggest a role of TDO in angiogenesis or vessel tonicity, as previously described for IDO1.

Tryptophanemia is controlled by a tryptophan-sensing mechanism ubiquitinating tryptophan 2,3-dioxygenase

“…Immunohistochemistry Using Chimeric Mouse-Rabbit mAb V. To detect TDO on mouse tissues, we replaced the Fc portion of the TDO clone V antibody (10) with that of a rabbit IgG to avoid detection of endogenous immunoglobulins with the secondary antibodies. For details on the construction of the chimeric antibody, see Hoffmann et al (36). Immunostaining was performed on 5-μm-thick paraffin sections as previously described (36).…”

“…For details on the construction of the chimeric antibody, see Hoffmann et al (36). Immunostaining was performed on 5-μm-thick paraffin sections as previously described (36). For TDO detection, the primary mouse-rabbit chimeric anti-TDO monoclonal antibody (mAb) V was diluted at 5 μg/mL in immunohistochemistry (IHC) diluent (ADI-950-244-0250, Enzo) and incubated for 1 h. Secondary staining was performed with EnVision+ HRP goat anti-rabbit Dako antibody (K4003, Agilent).…”

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder

“…Tryptophan 2,3-dioxygenase (TDO) is the other key enzyme in the KP, and it is mainly expressed in the liver and maintains systemic Trp levels by degrading excess dietary Trp under normal physiological conditions [ 59 , 60 ]. TDO is expressed pathologically in various tumors [ 61 ].…”

“…TDO was also identified in pericytes and interstitial syncytiotrophoblasts in the human placenta [ 63 ], and continuous TDO expression was observed in mouse decidual stromal cells, starting at E3.5 until gestation end. Despite the highly expressed TDO in decidual stromal cells, TDO-deficient and IDO1/TDO-double-deficient female mice did not show increased rates of miscarriage because of an absence of an increased immune attack against allogenic fetuses [ 60 ]. These results show that TDO may not be a dominant mechanism of maternal immunotolerance able to compensate for the absence of IDO1.…”

Attenuated retinoic acid signaling is among the early responses in mouse uterus approaching embryo attachment

“…TDO2 catalyzes the metabolism of tryptophan into kynurenine, and the kynurenine pathway is implicated in establishing and maintaining immune-privileged sites [15] . Despite normal fertility in the TDO2-deficient mice [14] , any potential contribution of TDO2 to immune regulation at the embryo attachment site cannot be entirely ruled out. Embryo implantation coincides with an increased number of immune cells in the stroma [16] , and immune-related genes, such as granzymes ( Gzmb , Gzmc , Gzmd ), were among the most upregulated genes in the pregnant uteri (Fig.…”