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

PLoS Pathogens

Arne Holmgren¹  Lucia Coppo¹  Xiaoyuan Ren¹  Jun Lu¹  Suman K. Vodnala²  Martin E. Rottenberg²  Chaniya Leepiyasakulchai²  Gabriela C. Olivera²  Krister Kristensson³ 

[1]Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

[2]Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

[3]Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

关键词: Parasitic diseases;    T cells;    Trypanosoma;    Macrophages;    Nitric oxide;    White blood cells;    RNA extraction;    Inflammation;   

DOI  :  10.1371/journal.ppat.1005442

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY