Public Library of Science, PLoS ONE, 6(10), p. e0131389, 2015
DOI: 10.1371/journal.pone.0131389
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The kynurenine pathway (KP) of tryptophan metabolism is widely recognized as having immunosuppressive and neuroactive properties via its main enzymes and metabolites, also known as kynurenines. This pathway, and its rate limiting enzyme, indoleamine-2,3-deoxygenase (IDO-1), are activated by inflammatory stimuli such as interferon gamma(IFN- Υ) and lipopolisaccharides (LPS). IDO-1 has immunosuppressive capacities, but its chronic activation can cause accumulation of damaging downstream kynurenines; as a result, in the last 20-30 years the KP has been linked to inflammatory and neurodegenerative conditions such as HIV-induced cognitive impairment, Huntington’s disease, Parkinson’s disease and multiple sclerosis (MS). Immune system cells are known to express the KP and in particular, peripheral blood mononuclear cells, such as monocytes and lymphocytes, are known to possess at least part of the machinery of this pathway. We believe that activation of the KP in monocytes during neuroinflammatory conditions, such as MS, can lead to accumulation of neurotoxin kynurenines in the CNS. We have therefore developed a novel methodological approach to quantify the expression of the KP enzymes IDO-1, kynurenine 3-mooxygenase (KMO) and quinolinate phosphorybosiltransferase (QPRT) in these cells via flow cytometry, combined with ultra high-performance liquid chromatography (UHPLC) and gas chromatography-mass spectrometry (GC-MS). Our group has shown a lack of up regulation of the main KP enzymes, IDO-1, KMO and QPRT in lymphocytes stimulated with IFN- Υ. We have also demonstrated that monocytes show a robust elevation of these enzymes in response to IFN- Υ. Recently we explored the possibility that the KP is differentially expressed by the different monocyte subsets. Monocytes represent a heterogeneous population divided into three subpopulation, namely the classical, intermediate and non-classical population. We have preliminary results showing differences in the up regulation of the enzyme IDO-1 in the monocyte subsets in response to stimulation with IFN- Υ and LPS. Confirmation of the hypothesis that non-classical monocytes present a higher up regulation of the KP and IDO-1 at basal conditions and in response to inflammatory stimulation, would have important therapeutic repercussions. In fact we could develop interventions aimed at decreasing the KP in non classical monocytes and reduce the accumulation of neurotoxic metabolites.