Kynurenine pathway metabolism in human blood–brain–barrier cells: implications for immune tolerance & neurotoxicity

Authors

  • Robert Owe-Young,

    1. University of New South Wales Centre for Immunology, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia
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  • Nicole L. Webster,

    1. AIDS Pathogenesis & Clinical Research Program, Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, Vic., Australia
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  • Muhammad Mukhtar,

    1. Centre for Human Retrovirology, Division of Infectious Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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    • 1

      Current address: Department of Biochemistry, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Rawalpindi 46300, Pakistan

  • Roger J. Pomerantz,

    1. Centre for Human Retrovirology, Division of Infectious Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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    • 2

      Current address: Tibotec, Inc., 1020 Stony Hill Rd., Yardley, PA 19067, USA.

  • George Smythe,

    1. Biomedical Mass Spectrometry Facility, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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  • David Walker,

    1. Department of Physiology, Monash University, Clayton, Vic., Australia
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  • Patricia J. Armati,

    1. Department of Medicine, Nerve Research Foundation, University of Sydney, New South Wales, Australia
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  • Suzanne M. Crowe,

    1. AIDS Pathogenesis & Clinical Research Program, Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, Vic., Australia
    2. Department of Medicine, Monash University, Melbourne, Vic., Australia
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  • Bruce J. Brew

    1. University of New South Wales Centre for Immunology, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia
    2. Departments of Neurology & HIV Medicine, St. Vincent’s Hospital, Darlinghurst, New South Wales, & National Centre in HIV Epidemiology & Clinical Research, Darlinghurst, New South Wales, Australia
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Address correspondence and reprint requests to Dr R. Owe-Young, Garvan Institute of Medical Research, 384 Victoria St. Darlinghurst, NSW 2010, Australia. E-mail: r.owe-young@garvan.org.au

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.

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