Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Since chemokines are involved in leukocyte recruitment into the inflamed brain, we hypothesized that COX-1 and COX-2 deletion will differentially modulate blood-brain barrier (BBB) permeability in response to LPS. Using quantitative magnetic resonance imaging, we found that LPS-induced BBB disruption was exacerbated in COX-2-/- vs. COX-2+/+ mice. In the hippocampus and cortex of LPS-treated mice, matrix metalloproteinase (MMP)-3 activity was significantly decreased in COX-1-/- mice, whereas in COX-2-/- mice the activity of both MMP-9 and MMP-3, known to mediate BBB breakdown, was increased. Brain mRNA expression of the leukocyte attracting chemokine Cxcl10, the intercellular interaction molecule Icam-1, the pan-leukocyte marker cd45 was increased in COX-2-/- vs. COX-2+/+ mice, whereas cxcl10 and cd45 mRNA expressions were decreased in COX-1-/- vs. COX-1+/+ mice after LPS. COX-derived prostaglandins promote the migration of several immune cells in vitro, however, the specific roles of COX-1 and -2 on leukocyte recruitment in vivo have not been investigated. To examine the specific effects of COX-1 or COX-2 deficiency on neuroinflammation-induced leukocyte infiltration, we used a model of LPS-induced innate immune activation in COX-1-/-, COX-2-/-, and their respective wild-type mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1-/- and increased in COX-2-/- mice, compared to their respective wild-type controls. This influx of leukocytes was accompanied by a marked disruption of blood-brain barrier and differential expression of chemokines. These results indicate that COX-1 and COX-2 differentially modulate leukocyte recruitment and BBB permeability during toll-like receptor 4-dependent innate immune activation, and suggest that inhibition of COX-1 activity is beneficial, whereas COX-2 inhibition may be detrimental, during a primary neuroinflammatory response. Furthermore, we used transgenic mice overexpressing human COX-2 via a neuron-specific Thy-1 promoter (TgCOX-2), causing elevated prostaglandins (PGs) levels to test whether neuronal COX-2 overexpression affects glial response to LPS. Relative to non-transgenic controls (NTg), 7 month-old TgCOX-2 did not show any basal neuroinflammation, as assessed by gene expression of markers of inflammation and oxidative stress, neuronal damage, as assessed by Fluoro-JadeB staining, or systemic inflammation, as assessed by plasma levels of IL-1beta and corticosterone. Twenty-four hours after LPS injection, all mice showed increased microglial activation, as indicated by Iba1 immunostaining, neuronal damage, mRNA expression of cytokines (TNF-alpha, IL-6), reactive oxygen expressing enzymes (iNOS and NADPH oxidase subunits), endogenous COX-2, cPLA(2) and mPGES-1, and hippocampal and cortical IL-1beta levels. However, the increases were similar in TgCOX-2 and NTg. In NTg, LPS increased brain PGE2 to the levels observed in TgCOX-2. These results suggest that PGs derived from neuronal COX-2 do not play a role in the neuroinflammatory response to acute activation of brain innate immunity. This is likely due to the direct effect of LPS on glial rather than neuronal cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000425-04
Application #
8148253
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2010
Total Cost
$354,880
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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Choi, Sang-Ho; Aid, Saba; Bosetti, Francesca (2009) The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci 30:174-81
Choi, Sang-Ho; Bosetti, Francesca (2009) Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid. Aging (Albany NY) 1:234-44
Aid, Saba; Langenbach, Robert; Bosetti, Francesca (2008) Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J Neuroinflammation 5:17
Choi, Sang-Ho; Langenbach, Robert; Bosetti, Francesca (2008) Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury. FASEB J 22:1491-501