Deficient Tryptophan Catabolism along the Kynurenine Pathway Reveals That the Epididymis Is in a Unique Tolerogenic State

Abstract

Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1 ؊/؊ -deficient mice. In the caput epididymis of Ido1؊/؊ animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.Indoleamine 2,3-dioxygenase (IDO) 3 (EC 1.13.11.42) is the first and rate-limiting enzyme in Trp catabolism through the kynurenine pathway (Fig. 1). IDO is a ubiquitously expressed cytoplasmic protein typically activated by interferons (IFNs) (1-5). There is ample evidence that IDO mediates potent immunosuppression in classical immune responses as well as in fetal tolerance, tumor immune resistance, and regulation of autoimmune responses (1-3, 6 -8).Thirty years ago, Yoshida et al. (9) reported that rodent epididymal protein extracts exhibited a high IDO activity. Later, Takikawa et al. (10) demonstrated that unlike the classical cytokine-mediated expression of IDO encountered in nearly all mammalian tissues, the epididymal expression of IDO was constitutive and independent of IFN-␥. More recently, we have shown that IDO is expressed in a regionalized manner by both the principal and the apical cells of the most proximal epididymal region, the caput epididymis. To gain insights into the functions of IDO and the intermediates of the kynurenine pathway in the physiology of the mammalian epididymis, we measured the expression of IDO and related enzymes as well as the abundance of kynurenines and other Trp metabolites in both wild type (WT) and Ido1 Ϫ/Ϫ male mice. These data were correlated with light and electron microscopic analyses of epididymal epithelium, sperm count, sperm morphology, and fertility.

Studies on Tissue and Cellular Distribution of Indoleamine 2,3-Dioxygenase 2

“…S2). These observations were in agreement with previous reports on IDO1 expression (Britan et al 2006;Dai and Zhu 2010;Jrad-Lamine et al 2011). In the caput of the epididymis, IDO1 and IDO2 showed different expression patterns in the segments. As shown in Fig.…”

“…We measured kynurenine concentration in the epididymis of IDO1 -/-. Although IDO2 expression was upregulated, the kynurenin concentration in IDO1 -/-decreased when compared with the WT (data not shown) (Jrad-Lamine et al 2011). Thus, the increased expression of IDO2 protein in the epididymis of IDO1 -/-was not sufficient to compensate for the production of kynurenine in the tissue.…”

“…These findings indicate that IDO1 in spermatozoa helps to control immunity. Therefore, the lack of IDO1 expression had no noticeable impact on overall male fertility but did induce a highly significant increase in both the number and the percentage of abnormal spermatozoa (Jrad-Lamine et al 2011).…”

The immunobiology of the mammalian epididymis: the black box is now open!

“…These observations reinforce the rather controversial idea that sperm selection during epididymal descent is a process that is partly under the control of the immune response [30]. To support the involvement of immune cells and immune responses in the epididymal selection of spermatozoa is our observation that the increased defective sperm counts found in Ido1 −/− cauda epididymides were paralleled with a very significant decrease in the cauda fluid leucocyte content [19]. …”

Why are epididymal tumours so rare?

“…Enzyme expression is highest in the caput and corpus, but absent from the cauda epididymidis. There is an increased expression of inflammatory markers in the caput region of IDO1-null mice, 115 attesting to a role for this enzyme in regulating local immune status. IDO-like proteins (INDOL, IDO2) have been found in man and mouse, with highest activity in the epididymis after the kidney.…”