Stroke upregulates TNFα transport across the blood-brain barrier

To determine how cytokine transport systems at the blood-brain barrier (BBB) participate in stroke progression and recovery, we generated a mouse model of transient middle cerebral artery occlusion (tMCAO). After 1 h of occlusion followed by nearly complete reperfusion, the neurological deficits lasted more than a week as shown by several behavioral tests. Despite the prominent infarct area indicated by reduced cerebral perfusion and confirmed by vital staining, the volume of distribution of 131I-albumin in various brain regions was not significantly altered over time (12 h to 14 days). In sharp contrast, the blood-to-brain permeation of 125I-TNFα was significantly increased 5 days after tMCAO. Furthermore, excess unlabeled TNFα abolished this enhanced 125I-TNFα uptake. Thus, not only did the known saturable transport system for TNFα persist, but it functioned at a higher capacity in tMCAO mice. Upregulation of TNFR1 and TNFR2 partially explains the increased transport, as mRNA for both receptors showed the most pronounced increase (15-fold and 30-fold, respectively) in the ischemic hemisphere 5-7 days after tMCAO. However, even in the hemisphere contralateral to the ischemia induced by stroke, there was increased TNFα transport. The bilateral increase in 125I-TNFα entry from blood to brain suggests that TNFα trafficking in cerebral endothelial cells is influenced by global mediators in addition to the transporting receptors. Given the known multiple modulatory effects of TNFα after stroke, the results indicate that the TNFα transport system at the BBB facilitates neuroplasticity and plays an important role in stroke recovery.