Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke
Article first published online: 25 OCT 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 70, Issue 4, pages 606–615, October 2011
How to Cite
Tang, X. N., Zheng, Z., Giffard, R. G. and Yenari, M. A. (2011), Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke. Ann Neurol., 70: 606–615. doi: 10.1002/ana.22476
- Issue published online: 25 OCT 2011
- Article first published online: 25 OCT 2011
- Accepted manuscript online: 11 MAY 2011 01:37PM EST
- Manuscript Accepted: 6 MAY 2011
- Manuscript Revised: 5 APR 2011
- Manuscript Received: 2 MAR 2011
Reperfusion after stroke leads to infiltration of inflammatory cells into the ischemic brain. Nicotinamide adenine dinucleotide phosphate oxidase (NOX2) is a major enzyme system that generates superoxide in immune cells. We studied the effect of NOX2 derived from the immune cells in the brain and in blood cells in experimental stroke.
To establish whether NOX2 plays a role in brain ischemia, strokes were created in mice, then mice were treated with the NOX2 inhibitor apocynin or vehicle and compared to mice deficient in NOX2's gp91 subunit and their wild-type littermates. To determine whether NOX2 in circulating cells versus brain resident cells contribute to ischemic injury, bone marrow chimeras were generated by transplanting bone marrow from wild-type or NOX2-deficient mice into NOX2 or wild-type hosts, respectively.
Apocynin and NOX2 deletion both significantly reduced infarct size, blood–brain barrier disruption, and hemorrhagic transformation of the infarcts, compared to untreated wild-type controls. This was associated with decreased matrix metalloproteinase 9 expression and reduced loss of tight junction proteins. NOX2-deficient mice receiving wild-type marrow had better outcomes compared to the wild-type mice receiving wild-type marrow. Interestingly, wild-type mice receiving NOX2-deficient marrow had even smaller infarct sizes and less hemorrhage than NOX2-deficient mice receiving wild-type marrow.
This indicates that NOX2, whether present in circulating cells or brain resident cells, contributes to ischemic brain injury and hemorrhage. However, NOX2 from the circulating cells contributed more to the exacerbation of stroke than that from brain resident cells. These data suggest the importance of targeting the peripheral immune system for treatment of stroke. Ann Neurol 2011;70:606–615