Current address: Department of Biochemistry, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi 46300, Pakistan
Kynurenine pathway metabolism in human blood–brain–barrier cells: implications for immune tolerance & neurotoxicity
Article first published online: 21 JAN 2008
© 2008 University of New South Wales
Journal of Neurochemistry
Volume 105, Issue 4, pages 1346–1357, May 2008
How to Cite
Owe-Young, R., Webster, N. L., Mukhtar, M., Pomerantz, R. J., Smythe, G., Walker, D., Armati, P. J., Crowe, S. M. and Brew, B. J. (2008), Kynurenine pathway metabolism in human blood–brain–barrier cells: implications for immune tolerance & neurotoxicity. Journal of Neurochemistry, 105: 1346–1357. doi: 10.1111/j.1471-4159.2008.05241.x
- Issue published online: 21 JAN 2008
- Article first published online: 21 JAN 2008
- Received August 20, 2007; revised manuscript received January 8, 2008; accepted January 11, 2008.
- Blood–brain barrier;
- immune tolerance;
- quinolinic acid;
- tryptophan metabolism
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.