Reactive oxygen species enhance the migration of monocytes across the blood-brain barrier in vitro

Reactive oxygen species (ROS) are involved in the pathogenesis of several i nflammatory and degenerative diseases, including multiple sclerosis (MS), a n inflammatory disease of the central nervous system. We investigated the p otential involvement of ROS in the interaction of monocytes with cerebral e ndothelium, because this is likely to be an early event in the development of MS lesions. ROS are produced via two main pathways, one involving NADPH oxidase complex and the other involving xanthine oxidase (XO). We examined the effects of ROS, ROS scavengers, and ROS inhibitors of both pathways on the migration of monocytes across the blood-brain barrier in vitro. Scaveng ers and inhibitors of XO predominantly inhibited monocyte migration, wherea s inhibitors and scavengers of the NADPH oxidase complex had no effect. Exp osure of cerebral endothelial cells (CEC) to superoxide (O-2(-)) resulted i n enhanced migration and adhesion of monocytes as well as disruption of the tight junctions, whereas hydroxyl radicals and hydrogen peroxide induced n o significant effect on these parameters. Underlying mechanisms of the obse rved changes were found to reside in the phospholipase C-mediated signal tr ansduction cascade, subsequent accumulation of inositol 1,4,5- trisphosphat e, and mobilization of intracellular calcium. We conclude that O-2(-) is a signaling molecule that is produced during the firm adhesion of monocytes t o CEC, which triggers cytoskeletal rearrangements allowing infiltration of monocytes into the brain.