Role of human brain microvascular endothelial cells during central nervous system infection

Rüdiger Adam; Daniel Rüssing; Ortwin Adams; Aziz Ailyati; Kwang Sik Kim; Horst Schroten; Walter Däubener

doi:10.1160/TH05-01-0053

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(02): 341-346
DOI: 10.1160/TH05-01-0053

Theme Issue Article

Schattauer GmbH

Role of human brain microvascular endothelial cells during central nervous system infection

Significance of indoleamine 2,3-dioxygenase in antimicrobial defence and immunoregulation

Rüdiger Adam

¹Pädiatrische Infektiologie, Klinik für Allgemeine Pädiatrie, Universitätsklinikum, Düsseldorf, Germany

,

Daniel Rüssing

²Institut für Medizinische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany

,

Ortwin Adams

³Institut für Virologie, Heinrich-Heine-Universität, Düsseldorf, Germany

,

Aziz Ailyati

²Institut für Medizinische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany

,

Kwang Sik Kim

⁴Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, USA

,

Horst Schroten

¹Pädiatrische Infektiologie, Klinik für Allgemeine Pädiatrie, Universitätsklinikum, Düsseldorf, Germany

,

Walter Däubener

²Institut für Medizinische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany

› Author Affiliations

Abstract

Summary

The cerebral endothelium is involved both in regulatinthinflux g e of immune cells into the brain and in modifying immunological reactions within the CNS. A number of human pathogens may cause encephalitis or meningitis when this important protective barrier is impaired. We have previously shown that interferon- γ activated human brain microvascular endothelial cells (HBMEC) restrict the growth of bacteria and parasites. We now provide evidence that HBMEC are also capable of inhibiting viral replication after stimulation with IFN-γ, an effect further augmented by costimulation with IL-1. This antiviral effect was completely blocked in the presence of L-tryptophan, indicating the induction of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) to be responsible for the observed antiviral effect. Apart from exerting antimicrobial effects tryptophan depletetion has also been described as a regulatory mechanism in T cell responses to both allo- and autoantigens. We were able to demonstrate that IDO mediated degradation of L-tryptohan in HBMEC is responsible for a significant reduction inT lymphocyte proliferation. Resupplementation of L-tryptophan and restoration of initial T cell responses demonstrated the central role of this essential amino acid in the reduction of T-cell proliferation. Brain endothelial cells appear to limit microbial expansion in the CNS by local degradation of tryptophan, thus acting in concert with other IDO-positive cell populations on the parenchymal side of the blood-brain barrier such as astrocytes, microglia and neurons. Since all dietary tryptophan must cross the blood-brain barrier, the microvascular endothelial cells may play a key role in restricting tryptophan influx from the bloodstream into the brain. As deleterious effects of brain infections can often be attributed to subsequently invading immune cells, an IDO-mediated reduction of lymphocyte proliferation may be beneficial for preventing collateral brain damage.

Keywords

Meningitis - encephalitis - IDO - kynurenine - herpes simplex virus

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References

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