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A Peroxynitrite-Dependent Pathway Is Responsible for Blood-Brain Barrier Permeability Changes during a Central Nervous System Inflammatory Response: TNF- Is Neither Necessary nor Sufficient¹

Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107

Elevated blood-brain barrier (BBB) permeability is associated with both the protective and pathological invasion of immune and inflammatory cells into CNS tissues. Although a variety of processes have been implicated in the changes at the BBB that result in the loss of integrity, there has been no consensus as to their induction. TNF- has often been proposed to be responsible for increased BBB permeability but there is accumulating evidence that peroxynitrite (ONOO^–)-dependent radicals may be the direct trigger. We demonstrate here that enhanced BBB permeability in mice, whether associated with rabies virus (RV) clearance or CNS autoimmunity, is unaltered in the absence of TNF-. Moreover, the induction of TNF- expression in CNS tissues by RV infection has no impact on BBB integrity in the absence of T cells. CD4 T cells are required to enhance BBB permeability in response to the CNS infection whereas CD8 T cells and B cells are not. Like CNS autoimmunity, elevated BBB permeability in response to RV infection is evidently mediated by ONOO^–. However, as opposed to the invading cells producing ONOO^– that have been implicated in the pathogenesis of CNS inflammation, during virus clearance ONOO^– is produced without pathological sequelae by IFN--stimulated neurovascular endothelial cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI09706 and a grant to the Biotechnology Foundation Laboratories from the Commonwealth of Pennsylvania.

² Address correspondence and reprint request to Dr. D. Craig Hooper, Department of Cancer Biology, Thomas Jefferson University, Jefferson Alumni Hall 454, 1020 Locust Street, Philadelphia, PA 19107. E-mail address: c_hooper{at}mail.jci.tju.edu

³ Abbreviations used in this paper: BBB, blood-brain barrier; RV, rabies virus; EAE, experimental allergic encephalomyelitis; iNOS, inducible NO synthase; i.n., intranasally; MOG, myelin oligodendrocyte glycoprotein; Na-F, sodium-fluorescein; NT, nitrotyrosine; UA, uric acid; DHR, dihydrorhodamine; IP-10, IFN--inducible protein-10; ONOO^–, peroxynitrite.

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				M. J. Fabis, T. W. Phares, R. B. Kean, H. Koprowski, and D. C. Hooper Blood-brain barrier changes and cell invasion differ between therapeutic immune clearance of neurotrophic virus and CNS autoimmunity PNAS, October 7, 2008; 105(40): 15511 - 15516. [Abstract] [Full Text] [PDF]