Upregulation of the Transport System for TNFa at the Blood-Brain Barrier

Abstract

The transport system for the cytokine tumor necrosis factor-a (TNFa) at the blood-brain barrier (BBB) enables an enhanced yet saturable entry of TNFa from blood to the CNS. This review focuses on the selective upregulation of the transport system for TNFa at the BBB that is specific for type of pathology, region, and time. The upregulation is reflected by increased CNS tissue uptake of radiolabeled TNFa after iv injection in mice and by inhibition of this increase with excess non-radiolabeled TNFa. (1) Spinal cord injury (SCI): upregulation of TNFa uptake after thoracic transection is seen in the delayed phase of BBB disruption at the lumbar spinal cord. Thoracic SCI by compression, however, has a longer lasting impact on TNFa transport that involves thoracic and lumbar spinal cord, in contrast to the upregulation confined to the lumbar region in lumbar SCI by compression. Regardless, the uptake of TNFa by spinal cord does not parallel BBB disruption as measured by the leakage of radiolabeled albumin. (2) Experimental autoimmune encephalomyelitis (EAE): the increase in the differential permeability to TNFa is seen in all CNS regions (brain and cervical, thoracic, and lumbar spinal cord) and has a distinct time course and reversibility. Exogenous TNFa has biphasic effects in modulating functional scores. The BBB, a dynamically regulated barrier, is actively involved in disease processes.