Abstract
Induction of the kynurenine pathway (KP) of tryptophan (TRP) catabolism has been proposed to contribute to T cell dysfunction during human/simian immunodeficiency virus (SIV) infection via depletion of local TRP levels and production of immunomodulatory KP metabolites. However, while changes in TRP and KP metabolites have been observed in plasma, their levels in lymphoid tissues and levels of enzymes downstream of indoleamine 2,3-dioxygenase (IDO1) have been relatively unexplored. We used our SIV-infected pigtailed macaque model to analyze longitudinal changes in KP metabolites and enzymes by gas chromatography/mass spectrometry and NanoString nCounter gene expression analysis, respectively, in spleen and blood compared to changes previously established in brain and CSF. We found that TRP levels were remarkably stable in tissue sites despite robust depletion in the circulating plasma and CSF. We also demonstrated that intracellular TRP reserves were maintained in cultured cells even in the presence of depleted extracellular TRP levels. Kynurenine (KYN), 3-hydroxykynurenine, quinolinic acid, and the KP enzymes all displayed highly divergent patterns in the sites examined, though IDO1 expression always correlated with local KYN/TRP ratios. Finally, we demonstrated by fluorescence-activated cell sorting that myeloid dendritic cells and cells of monocytic lineage were the highest producers of IDO1 in chronically infected spleens. Overall, our study reveals insights into the tissue-specific regulation of KP enzymes and metabolites and, in particular, highlights the multiple mechanisms by which cells and tissues seek to prevent TRP starvation during inflammation.
Highlights
Induction of the kynurenine pathway (KP) of tryptophan (TRP) catabolism is thought to play a major role in immune dysfunction in human immunodeficiency virus (HIV)-infected individuals, even those on combination anti-retroviral therapy [1,2,3,4,5,6,7,8]
Splenic mononuclear cell (MNC) from two of these infected animals underwent cell sorting by fluorescence activated cell sorting (FACS) and qRT-PCR for cell-specific IDO1 expression. From these FACS-sorted cells, we found that myeloid dendritic cells and CD14+ monocytes from the chronically infected spleens maintained their ability to express high levels of IDO1 mRNA (Figure 7B)
We did not find any significant reductions in TRP in either the spleen or brain at any time point during infection, despite TRP levels in the plasma and CSF being reduced by up to 50%, on par with changes reported in plasma and CSF of HIV-infected patients [14, 51, 52]
Summary
Induction of the kynurenine pathway (KP) of tryptophan (TRP) catabolism is thought to play a major role in immune dysfunction in human immunodeficiency virus (HIV)-infected individuals, even those on combination anti-retroviral therapy (cART) [1,2,3,4,5,6,7,8]. In addition to the consequences of TRP depletion, increased TRP catabolism down the KP leads to generation of metabolites that have immunomodulatory capabilities, which include prevention of T cell proliferation [kynurenine (KYN) and picolonic acid] [10]; conversion of naïve T cells or proinflammatory Th17 cells into regulatory T cells following interactions at the aryl hydrocarbon receptor, which may increase susceptibility to opportunistic infections at mucosal surfaces [KYN and 3-hydroxy anthranilic acid (3HANA)] [2, 11]; and direct apoptosis of activated T cells (3HANA and cinnabarinic acid) [12, 13]. While expression of the rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has been repeatedly examined in the context of HIV/SIV infection, the regulation of downstream enzymes of the KP has been relatively unexplored
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