Cyclooxygenases-1 and-2 differentially modulate leukocyte recruitment into the inflamed brain

Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Cyclooxygenase (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 intracerebroventricular lipopolysaccharide (LPS)-induced neuroinflammation in COX-1(-/-), COX-2(-/-), and their respective wild-type (WT) ((+/+)) mice. After LPS, leukocyte infiltration and inflammatory response were attenuated in COX-1(-/-) and increased in COX-2(-/-) mice, compared with their respective WT 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 deletion differentially modulate leukocyte recruitment during neuroinflammation, and suggest that inhibition of COX-1 activity is beneficial, whereas COX-2 inhibition is detrimental, during a primary neuroinflammatory response. The Pharmacogenomics Journal (2010) 10, 448-457; doi:10.1038/tpj.2009.68; published online 29 December 2009