# Biological actions of endogenous Kynurenine-derived electrophiles

> **NIH NIH R56** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $179,673

## Abstract

The kynurenine pathway catabolizes over 95% of all tryptophan primarily through the actions of
tryptophan 2,3-dioxygenase 2 (TDO2) in hepatocytes and indoleamine 2,3-dioxygenese 1 (IDO1) in myeloid
leukocytes. Increased kynurenine synthesis in dendritic cells (DC) secondary to IDO1 upregulation is strongly
linked with the generation of a tolerogenic phenotype by promoting anti-inflammatory signaling, regulatory T cell
(Treg) polarization and immune tolerance, an attenuated inflammatory response instigated by immune cells that
are repeatedly exposed to TLR ligands. However, while the pathophysiologic relevance of this pathway is well-
established, the mechanism behind the immunomodulatory effects of kynurenine remain poorly defined. Using
metabolomic approaches, we found that systemic increases in kynurenine secondary to either exogenous
supplementation or chronic inflammation are associated with the formation of a novel signaling-active
kynurenine-derived electrophile. This mediator, potently inhibits TLR4-dependent NF-κB signaling in primary
macrophages and attenuates inflammatory responses in endotoxin-challenged mice. In addition, the novel
kynurenine-derived electrophile engages AhR signaling with 50-fold higher potency than its kynurenine
precursor, suggesting a potential pro-tolerogenic role in DC and T-cells. Specifically designed state-of-the-art
LC-MS/MS assays will enable the quantification of this novel derivative in the context of other kynurenine
pathway metabolites in activated and non-activated myeloid leukocytes as well as the elucidation of uptake and
export mechanisms. The kynurenine-derived electrophile is a charged amino acid at physiological pH, thus a
cell-permeable alkyl-esterified analogue will be synthesized to further define its signaling mechanisms and
therapeutic potential in the absence of the rate-limiting effects of active cellular transport and potential
competition by other amino acids present in the extracellular milieu. Primary cells derived from pathway-specific
knock-out animals and novel bio-orthogonal labeling strategies will be harnessed to define the mechanistic basis
of the anti-inflammatory actions of the kynurenine-derived electrophile both in terms of the modulation of specific
signaling pathways and its effects on inflammation-elicited changes in energy metabolism. Finally, the potential
of the kynurenine-derived electrophile to promote tolerogenic responses will be established assessing in vitro T
cell polarization and in vivo models of endotoxin resistance and tolerance. This Research Plan will reveal specific
immunomodulatory actions of the kynurenine pathway and may potentially lead to the development of related
pharmacological interventions for dysregulated immune responses such as chronic inflammation, autoimmune
diseases, cancer, and allograft rejection.

## Key facts

- **NIH application ID:** 10724511
- **Project number:** 7R56AI165479-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Dario A Vitturi
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $179,673
- **Award type:** 7
- **Project period:** 2022-02-09 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10724511

## Citation

> US National Institutes of Health, RePORTER application 10724511, Biological actions of endogenous Kynurenine-derived electrophiles (7R56AI165479-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10724511. Licensed CC0.

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