Tumor necrosis factor and stroke: role of the blood-brain barrier

The progression and outcome of stroke is affected by the intricate relationship between the blood-brain barrier (BBB) and tumor necrosis factor alpha (TNFalpha). TNFalpha crosses the intact BBB by a receptor-mediated transport system that is upregulated by CNS trauma and inflammation. In this review, we discuss intracellular trafficking and transcytosis of TNFalpha, regulation of TNFalpha transport after stroke, and the effects of TNFalpha on stroke preconditioning. TNFalpha can activate cytoprotective pathways by pretreatment or persistent exposure to low doses. This explains the paradoxical observation that transport of this proinflammatory cytokine improves the survival and function of hypoxic cells and of mice with stroke. The dual effects of TNFalpha may be related to differential regulation of TNFalpha trafficking downstream to TNFR1 and TNFR2 receptors. As we better understand how peripheral TNFalpha affects its own transport and modulates neuroregeneration, we may be in a better position to pharmacologically manipulate its regulatory transport system to treat stroke.