Using microarray technology, we reported that our model of intracerebroventricular injection of lipopolysaccharide (LPS) results in a robust inflammatory response in the brain, with an increased expression of Gene Ontology (GO) terms for inflammation and the ribosome and a decreased expression of GO terms associated with learning and memory. We showed that cyclooxygenase (COX)-1-/- mice have a significant reduction in brain inflammatory response and oxidative damage after LPS. The protection was attributed to attenuation of microglial activation, a critical process in the initiation of inflammation, and to a reduction of inflammatory mediators such as prostaglandins, cytokines, chemokines and of protein oxidation, critical factors contributing to the secondary progression of the inflammatory reaction and oxidative damage. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000425-03
Application #
7963968
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2009
Total Cost
$326,870
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Russo, Isabella; Amornphimoltham, Panomwat; Weigert, Roberto et al. (2011) Cyclooxygenase-1 is involved in the inhibition of hippocampal neurogenesis after lipopolysaccharide-induced neuroinflammation. Cell Cycle 10:2568-73
Aid, Saba; Silva, Afonso C; Candelario-Jalil, Eduardo et al. (2010) Cyclooxygenase-1 and -2 differentially modulate lipopolysaccharide-induced blood-brain barrier disruption through matrix metalloproteinase activity. J Cereb Blood Flow Metab 30:370-80
Aid, Saba; Parikh, Nishant; Palumbo, Sara et al. (2010) Neuronal overexpression of cyclooxygenase-2 does not alter the neuroinflammatory response during brain innate immune activation. Neurosci Lett 478:113-8
Choi, S-H; Aid, S; Choi, U et al. (2010) Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain. Pharmacogenomics J 10:448-57
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