Kynurenine pathway metabolism in human blood-brain-barrier cells: implications for immune tolerance & neurotoxicity
Author
Owe-Young, R; Webster, NL; Mukhtar, M; Pomerantz, RJ; Smythe, G; Walker, D; Armati, PJ; Crowe, SM; Brew, BJDate
2008-05-01Source Title
JOURNAL OF NEUROCHEMISTRYPublisher
BLACKWELL PUBLISHINGUniversity of Melbourne Author/s
Webster, NicoleAffiliation
Microbiology And ImmunologyMetadata
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Journal ArticleCitations
Owe-Young, R., Webster, N. L., Mukhtar, M., Pomerantz, R. J., Smythe, G., Walker, D., Armati, P. J., Crowe, S. M. & Brew, B. J. (2008). Kynurenine pathway metabolism in human blood-brain-barrier cells: implications for immune tolerance & neurotoxicity. JOURNAL OF NEUROCHEMISTRY, 105 (4), pp.1346-1357. https://doi.org/10.1111/j.1471-4159.2008.05241.x.Access Status
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C1 - Journal Articles Refereed
Abstract
The catabolic pathway of l-tryptophan (l-trp), known as the kynurenine pathway (KP), has been implicated in the pathogenesis of a wide range of brain diseases through its ability to lead to immune tolerance and neurotoxicity. As endothelial cells (ECs) and pericytes of the blood-brain-barrier (BBB) are among the first brain-associated cells that a blood-borne pathogen would encounter, we sought to determine their expression of the KP. Using RT-PCR and HPLC/GC-MS, we show that BBB ECs and pericytes constitutively express components of the KP. BBB ECs constitutively synthesized kynurenic acid, and after immune activation, kynurenine (KYN), which is secreted basolaterally. BBB pericytes produced small amounts of picolinic acid and after immune activation, KYN. These results have significant implications for the pathogenesis of inflammatory brain diseases in general, particularly human immunodeficiency virus (HIV)-related brain disease. Kynurenine pathway activation at the BBB results in local immune tolerance and neurotoxicity: the basolateral secretion of excess KYN can be further metabolized by perivascular macrophages and microglia with synthesis of quinolinic acid. The results point to a mechanism whereby a systemic inflammatory signal can be transduced across an intact BBB to cause local neurotoxicity.
Keywords
Cellular Immunology; Immune System and AllergyExport Reference in RIS Format
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