A peroxynitrite-dependent pathway is responsible for blood-brain barrier permeability changes during a central nervous system inflammatory response: TNF-α is neither necessary nor sufficient

Timothy W. Phares, Marzena J. Fabis, Christine M. Brimer, Rhonda B. Kean, D. Craig Hooper

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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-α 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-α. Moreover, the induction of TNF-α 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 CDS 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-γ-stimulated neurovascular endothelial cells.

Original languageEnglish
Pages (from-to)7334-7343
Number of pages10
JournalJournal of Immunology
Volume178
Issue number11
DOIs
StatePublished - 1 Jun 2007
Externally publishedYes

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