Role of indoleamine 2,3-dioxygenase in testicular immune-privilege

Abstract

Male meiotic germ cell including the spermatozoa represent a great challenge to the immune system, as they appear long after the establishment of normal immune tolerance mechanisms. The capacity of the testes to tolerate autoantigenic germ cells as well as survival of allogeneic organ engrafted in the testicular interstitium have led to consider the testis an immunologically privileged site. Disruption of this immune privilege following trauma, tumor, or autoimmune orchitis often results in male infertility. Strong evidence indicates that indoleamine 2,3-dioxygenase (IDO) has been implicated in fetal and allograft tolerance, tumor immune resistance, and regulation of autoimmune diseases. IDO and tryptophan 2,3-dioxygenase (TDO) catalyze the same rate-limiting step of tryptophan metabolism along a common pathway, which leads to tryptophan starvation and generation of catabolites collectively known as kynurenines. However, the relevance of tryptophan metabolism in testis pathophysiology has not yet been explored. Here we assessed the in vivo role of IDO/TDO in experimental autoimmune orchitis (EAO), a model of autoimmune testicular inflammation and immunologically impaired spermatogenesis. EAO was induced in adult Wistar rats with testicular homogenate and adjuvants. Control (C) rats injected with saline and adjuvants and normal untreated rats (N) were also studied. mRNA expression of IDO decreased in whole testes and in isolated Sertoli cells during EAO. TDO and IDO localization and level of expression in the testis were analyzed by immunostaining and Western blot. TDO is expressed in granulomas from EAO rats, and similar protein levels were observed in N, C, and EAO groups. IDO was detected in mononuclear and endothelial cells and reduced IDO expression was detected in EAO group compared to N and C rats. This phenomenon was concomitant with a significant reduction of IDO activity in EAO testis measured by tryptophan and kynurenine concentrations (HPLC). Finally, in vivo inhibition of IDO with 1-methyl-tryptophan increased severity of the disease, demonstrating down regulation of IDO-based tolerance when testicular immune regulation was disrupted. We present evidence that an IDO-based mechanism is involved in testicular immune privilege.

Pathomechanisms of Autoimmune Based Testicular Inflammation

“…Indoleamine-2,3-dioxygenase (IDO) expression in porcine Sertoli cells and the ability of these cells to restore immune tolerance in NOD mice ( 42 ) point to a role of IDO in testis immune privilege. Current findings from functional in vivo experimental studies confirm that tryptophan metabolism modulates inflammatory immune response to spermatic antigens ( 43 ).…”

T Lymphocytes and Testicular Immunity: A New Insight into Immune Regulation in Testes

“…Fallarino et al found that SCs can produce indoleamine 2, 3-dioxygenase (IDO), TGF-β, and complementary inhibitors, and they are an important inducer of inflammation and the subsequent immune response, when they are used as isolated SCs to treat experimental type 1 diabetes [112]. The most recent data further prove the immune regulatory role of IDO in EAO rats [116]. Microarray analyses and qRT-PCR in SCs demonstrate that SCs express serine protease inhibitor (SERPIN)G1, which targets the initial step of the complementary cascade activation, thus preventing further amplification [117].…”

Impacts of Immunometabolism on Male Reproduction

“…IDO is reported to induce DCs to initiate immune tolerance and to stimulate the development of Tregs in tumors and pregnant uterus both are immunologically privileged site like testes (117)(118)(119). Recently, the IDO-based mechanism has also been identified to be involved in testicular immune privilege (120). The expression of IDO is rapidly increased when DCs suffer from LPS/IFN-g-stimulation, leading to limited microbial growth and reduced injurious hyperinflammatory responses (121,122).…”

“…The expression of IDO is rapidly increased when DCs suffer from LPS/IFN-γ-stimulation, leading to limited microbial growth and reduced injurious hyperinflammatory responses ( 121 , 122 ). However, testicular DCs mildly expressed IDO, meanwhile IDO activity is reduced in EAO rat ( 120 , 123 ). These differences might be attributed to the fact that the Sertoli cells indirectly inhibit LPS-induced DCs maturation through paracrine effect.…”