Nitric Oxide Protects against Infection-Induced Neuroinflammation by Preserving the Stability of the Blood-Brain Barrier

Nitric oxide (NO) generated by inducible NO synthase (iNOS) is critical for defense against intracellular pathogens but may mediate inflammatory tissue damage. To elucidate the role of iNOS in neuroinflammation, infections with encephalitogenic Trypanosoma brucei parasites were compared in inos(-/-)...

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Published in:PLoS pathogens 2016-02, Vol.12 (2), p.e1005442-e1005442
Main Authors: Olivera, Gabriela C, Ren, Xiaoyuan, Vodnala, Suman K, Lu, Jun, Coppo, Lucia, Leepiyasakulchai, Chaniya, Holmgren, Arne, Kristensson, Krister, Rottenberg, Martin E
Format: Article
Language:English
Subjects:
Animals
Biology and Life Sciences
Blood-brain barrier
Blood-Brain Barrier - metabolism
Brain
Cytokines - metabolism
Development and progression
Encephalitis - metabolism
Enzymes
Experiments
Genetic aspects
Health aspects
Immune response
Infections
Lymphocytes
Macrophages - metabolism
Macrophages, Peritoneal - metabolism
Medicin och hälsovetenskap
Medicine and Health Sciences
Mice, Knockout
Nervous system
Nervous system diseases
Nitric oxide
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - metabolism
Parasites
Permeability
Prevention
Research and analysis methods
Rodents
Trypanosoma brucei brucei - metabolism
Trypanosomiasis
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Summary:Nitric oxide (NO) generated by inducible NO synthase (iNOS) is critical for defense against intracellular pathogens but may mediate inflammatory tissue damage. To elucidate the role of iNOS in neuroinflammation, infections with encephalitogenic Trypanosoma brucei parasites were compared in inos(-/-) and wild-type mice. Inos(-/-) mice showed enhanced brain invasion by parasites and T cells, and elevated protein permeability of cerebral vessels, but similar parasitemia levels. Trypanosome infection stimulated T cell- and TNF-mediated iNOS expression in perivascular macrophages. NO nitrosylated and inactivated pro-inflammatory molecules such as NF-κΒp65, and reduced TNF expression and signalling. iNOS-derived NO hampered both TNF- and T cell-mediated parasite brain invasion. In inos(-/-) mice, TNF stimulated MMP, including MMP9 activity that increased cerebral vessel permeability. Thus, iNOS-generated NO by perivascular macrophages, strategically located at sites of leukocyte brain penetration, can serve as a negative feed-back regulator that prevents unlimited influx of inflammatory cells by restoring the integrity of the blood-brain barrier.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1005442