TNF-α–secreting monocytes are recruited into the brain of cholestatic mice

Authors

  • Steven M. Kerfoot,

    1. Liver Unit, Immunology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada
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  • Charlotte D'Mello,

    1. Liver Unit, Gastroenterology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada
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  • Henry Nguyen,

    1. Liver Unit, Gastroenterology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada
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  • Maureen N. Ajuebor,

    1. Liver Unit, Gastroenterology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada
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  • Paul Kubes,

    1. Liver Unit, Immunology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada
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    • P. K. is a CIHR and an AHFMR Scientist.

  • Tai Le,

    1. Liver Unit, Gastroenterology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada
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  • Mark G. Swain

    Corresponding author
    1. Liver Unit, Gastroenterology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada
    • University of Calgary, Calgary, Alberta, Canada T2N 4N1
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    • fax: 403-270-0995

    • M.G. S. is a CIHR Investigator and an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar.


  • See Editorial on Page 20

  • Potential conflict of interest: Nothing to report.

Abstract

Signaling occurs between the liver and brain in cholestatic liver disease, giving rise to sickness behaviors such as fatigue. However, the signaling pathways involved are poorly defined. Circulating inflammatory mediator levels are increased in cholestasis, leading to speculation that they may be capable of activating circulating immune cells that subsequently could gain access to the brain. Indeed, we have identified that at day 10 after bile duct resection–induced cholestasis, there is activation of circulating monocytes that express tumor necrosis factor α (TNF-α) in conjunction with increased expression of adhesion molecules by cerebral endothelium. Moreover, using intravital microscopy, we have identified markedly enhanced leukocytes rolling along cerebral endothelial cells, mediated by P-selectin, in bile duct–resected (BDR) but not control mice. In addition, we have identified increased infiltration of monocytes (but not lymphocytes) into the brains of BDR mice and found that these infiltrating monocytes produce TNF-α. Furthermore, infiltration of TNF-α–secreting monocytes into the brains of cholestatic mice is associated with a broad activation of resident brain macrophages to produce TNF-α. In conclusion, cholestasis is associated with an activation of cerebral endothelium that recruits TNF-α–producing monocytes into the brain. We hypothesize that enhanced TNF-α release within the brain may contribute to the development of cholestasis-associated sickness behaviors, including fatigue. (HEPATOLOGY 2006;43:154–162.)

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