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Published on: November 5, 2019
Interferon-γ-Induced Nitric Oxide Synthase-2 Contributes to Blood/Brain Barrier Dysfunction and Acute Mortality in
Belinda Yau1, Andrew J Mitchell1,2, Lay Khoon Too1
11 Molecular Immunopathology Unit, School of Medical Sciences, Sydney Medical School, University of Sydney , Sydney, New South Wales, Australia .
Abstract:
The proinflammatory cytokine interferon-gamma (IFNγ) recently was shown to play a crucial role in experimental pneumococcal meningitis (PM) pathogenesis, and we aimed in this study to investigate IFNγ-driven nitric oxide synthase-2 (NOS2)-mediated pathogenesis of murine PM. We demonstrate that costimulation of toll-like receptors and IFNγ receptors was synergistic for NOS2 expression in cultured murine microglia. Using an experimental PM model, wild-type mice treated with anti-IFNγ antibody, as well as IFNγ and NOS2 gene knockout (GKO) mice, were inoculated intracerebroventricularly with 10(3) colony-forming units of Streptococcus pneumoniae (WU2 strain). Mice were monitored daily during a 200-h disease course to assess survival rate and blood-brain barrier (BBB) permeability measured at 48 h. IFNγ deficiency was protective in PM, with an approximate 3-fold increase in survival rates in both antibody-treated and IFNγ GKO mice compared to controls (P < 0.01). At 48 h postinoculation, brain NOS2 mRNA expression was significantly increased in an IFNγ-dependent manner. Mortality was significantly delayed in NOS2 GKO mice compared to controls (P < 0.01), and BBB dysfunction was reduced by 54% in IFNγ GKO mice and abolished in NOS2 GKO. These data suggest that IFNγ-dependent expression of NOS2 in the brain contributes to BBB breakdown and early mortality in murine PM.
Insights
Interferon-gamma (IFNγ) drives nitric oxide synthase-2 (NOS2) expression, worsening pneumococcal meningitis (PM) in mice. Blocking IFNγ or NOS2 improved survival and reduced blood-brain barrier damage, highlighting a key pathogenic pathway.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- The proinflammatory cytokine interferon-gamma (IFNγ) is implicated in experimental pneumococcal meningitis (PM) pathogenesis.
- Investigating the role of IFNγ-driven nitric oxide synthase-2 (NOS2) in murine PM is crucial.
Purpose of the Study:
- To elucidate the role of IFNγ-driven NOS2 in the pathogenesis of experimental murine PM.
- To assess the impact of IFNγ and NOS2 on survival rates and blood-brain barrier (BBB) permeability during PM.
Main Methods:
- Utilized an experimental murine PM model with Streptococcus pneumoniae (WU2 strain).
- Employed wild-type mice, anti-IFNγ antibody treatment, and IFNγ and NOS2 gene knockout (GKO) mice.
- Monitored survival rates and measured BBB permeability at 48 hours post-inoculation.
Main Results:
- IFNγ deficiency significantly increased survival rates (approx. 3-fold) in PM models.
- Brain NOS2 mRNA expression was elevated in an IFNγ-dependent manner.
- NOS2 GKO mice showed delayed mortality, and both IFNγ GKO and NOS2 GKO mice exhibited reduced BBB dysfunction.
Conclusions:
- IFNγ-dependent NOS2 expression contributes to BBB breakdown in murine PM.
- Targeting the IFNγ-NOS2 pathway may offer therapeutic strategies for PM.
- IFNγ plays a critical role in PM pathogenesis by inducing NOS2, leading to BBB disruption and mortality.
