Cyclooxygenase-1 and -2 differentially modulate lipopolysaccharide-induced blood-brain barrier disruption through matrix metalloproteinase activity.
Cyclooxygenases (COX) -1 and -2 are key regulators of innate immune responses. We recently demonstrated that the expression of proinflammatory cytokines and chemokines is reduced in COX-1 null ((-/-)), and increased in COX-2(-/-) mice compared with their respective wild type controls during lipopolysaccharide (LPS)-induced innate immune activation. As 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. In the present study, using quantitative magnetic resonance imaging, we found that LPS-induced BBB disruption was exacerbated in COX-2(-/-) versus 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(-/-) versus COX-2(+/+) mice, whereas Cxcl10 and Cd45 mRNA expression was decreased in COX-1(-/-) versus COX-1(+/+) mice after LPS. Altogether, these results indicate that COX-2 activity modulates MMP-9 and-3 activities and is necessary to maintain BBB integrity during toll-like receptor 4-dependent innate immune activation.
Brain Physiology and Metabolism Section, National Institute on Aging, NIH, Bethesda, Maryland 20892, USA.
Saba
S
Aid
Afonso C
AC
Silva
Eduardo
E
Candelario-Jalil
Sang-Ho
SH
Choi
Gary A
GA
Rosenberg
Francesca
F
Bosetti
D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002199:Capillary Permeability; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D008279:Magnetic Resonance Imaging; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008070:Lipopolysaccharides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9