Abstract
Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-l-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.
Highlights
Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance
We report the discovery of the previously undescribed biogenic amine 3-hydroxykynurenine (3-HKA), which is produced via a lateral branch of the IDO1 pathway in dendritic cells (DCs), and at high levels in lymphatic endothelial cells (LEC) and human tumor cell lines. 3-HKA inhibits the activation of proinflammatory STAT1 and NF-kB pathways in mouse and human DCs and has therapeutic effects in experimental models of psoriasis and nephrotoxic nephritis
In the primary pathway Trp is metabolized to N-formyl-kynurenine, which is converted to kynurenine and 3-hydroxy-kynurenine, the major metabolites observed in DCs
Summary
Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Metabolomic analysis detected low nanomolar amount of 3-HKA in unstimulated cells which increased following IFN-γ treatment (Fig. 2d). Our results on both mouse and human monocytederived DCs indicated that 3-HKA is a biogenic amine since it inhibits IFN-γ-mediated JAK-STAT1 and NF-κΒ activation, which results in reduced secretion of proinflammatory cytokines and chemokines (Fig. 6 and Supplementary Data 2).
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