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

Abstract

Peripheral leukocyte recruitment in neuroinflammatory conditions can exacerbate brain tissue damage by releasing cytotoxic mediators and by increasing vascular permeability. Cyclooxygenase (COX)-derived prostaglan-dins 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.

Brain Barriers and the Acute-Phase Response

“…Additionally, the development of selective COX-2 inhibitors further suggests an important role for this cyclooxygenase in the BBB in response to acute inflammation; specifically, its inhibition lead to a decrease in the expression of tight junctions proteins in the endothelial cells of the barrier (Germann et al, 2008). In accordance, it has also been shown that COX-2 null-mice exhibit an increase in LPS-induced BBB disruption, mediated by an increase in matrix metalloproteinases 9 and 3 activities (Choi et al, 2010). These results further support the hypothesis that COX-2 may mediate the neuroinflammatory response, especially in maintaining the integrity of the neurovascular unit (Choi et al, 2010).…”

“…In accordance, it has also been shown that COX-2 null-mice exhibit an increase in LPS-induced BBB disruption, mediated by an increase in matrix metalloproteinases 9 and 3 activities (Choi et al, 2010). These results further support the hypothesis that COX-2 may mediate the neuroinflammatory response, especially in maintaining the integrity of the neurovascular unit (Choi et al, 2010). Finally, cyclooxygenases can differentially modulate leukocyte recruitment into the inflamed brain (Choi et al, 2010).…”

Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110γ PI3K Signaling and Impairs Cell Adhesion and Migration

“…Previous studies reported that Cox-derived PGs can modulate leukocyte migration to the inflamed tissue (52). Mice deficient in Cox-2 or mPGES-1, a downstream PG synthase, have a reduced recruitment of leukocytes to the inflammatory foci, as shown in different mouse models, including thioglycolate- induced peritonitis (53,54).…”

Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes

“…In contrast, in neurodegenerative diseases, COX-2 inhibitors are not protective in mouse models of Alzheimer disease (7) and did not show benefits in clinical trials in Alzheimer disease patients (8) or in patients with mild cognitive impairment (9). Furthermore, COX-2 inhibitors increase the risk of cardiovascular and cerebrovascular pathology (10), and Cox-2-deficient mice show exacerbated brain inflammation, leukocyte infiltration, and blood-brain barrier damage after exposure to the bacterial lipopolysaccharide (LPS) (11)(12)(13)(14)(15), suggesting some beneficial action of COX-2 in inflammation. Furthermore, COX-2 might contribute to neurovascular coupling because COX-2 inhibitors abrogate the increases in cerebral blood flow (CBF) induced by neuronal activation in rats (16).…”