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

PLoS Pathog. 2016 Feb 25;12(2):e1005442. doi: 10.1371/journal.ppat.1005442. eCollection 2016 Feb.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Cytokines / metabolism
  • Encephalitis / metabolism*
  • Macrophages / metabolism*
  • Macrophages, Peritoneal / metabolism*
  • Mice, Knockout
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Trypanosoma brucei brucei / metabolism


  • Cytokines
  • Nitric Oxide
  • Nitric Oxide Synthase Type II

Grant support

This study was supported by grants from the Swedish Research Council, EuroNet-Neuron program, 2014-16/529-2014-7552/ERA-Net Neuron and the Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.