Divergent Roles of Glutathione Peroxidase-1 (Gpx1) in Regulation of Leukocyte-Endothelial Cell Interactions in the Inflamed Cerebral Microvasculature

Abstract

The aim of this study was to assess the ability of Gpx1 to regulate leukocyte-endothelial cell interactions in the cerebral microcirculation under inflammatory conditions associated with oxidative stress. To induce cerebral inflammation, wild-type and Gpx1(-/-) mice underwent systemic treatment with TNF or transient focal cerebral ischemia via MCAO. Leukocyte rolling and adhesion in cerebral postcapillary venules were assessed by intravital microscopy. Absence of Gpx1(-/-) resulted in increased cerebral oxidant production in response to TNF. Under these conditions, leukocyte rolling in cerebral venules was significantly elevated in Gpx1(-/-) mice, whereas leukocyte adhesion was lower than that in wild-type mice. Despite this, expression of key adhesion molecules did not differ between the strains. Following MCAO, Gpx1(-/-) mice displayed significant reductions in rolling and adhesion associated with severe blood flow restriction. In contrast, following treatment with the anti-oxidant ebselen to equalize postischemic cerebral blood flow in wild-type and Gpx1(-/-) mice, absence of Gpx1 was associated with significant elevations in leukocyte interactions. These data show that under some inflammatory conditions, Gpx1 regulates leukocyte-endothelial cell interactions in the cerebral microvasculature, but that this is affected by the nature of the inflammatory insult.