Receptor-mediated transport of LIF across blood–spinal cord barrier is upregulated after spinal cord injury

Abstract

Leukemia inhibitory factor (LIF) crosses the normal blood–brain and blood–spinal cord barrier (BBB) by a saturable transport system [Pan, W., Kastin, A.J., Brennan, J.M., 2000. Saturable entry of leukemia inhibitory factor from blood to the central nervous system. J. Neuroimmunol. 106, 172–180]. Since LIF is a cytokine beneficial to spinal cord regeneration, understanding the regulation of its transport across the injured BBB may help in the design of strategies for the treatment of spinal cord injury (SCI). In this study, we initially showed that transport of LIF is mediated by its specific receptor LIFRα (gp190), using both adult mice and monolayers of mouse brain microvessel endothelial cells. Permeation of radioactively labeled LIF was inhibited not only by excess unlabeled LIF, but also by a blocking antibody to the extracellular domain of gp190 LIFRα receptor. This showed that the saturable transport of LIF across the BBB involves LIFRα. We then tested the hypothesis that this transport system can be upregulated after SCI. SCI was generated by an established compression method at the upper lumbar level. Transport was studied 1 week after SCI, a time of tissue repair following ischemia and inflammation. Spinal cord uptake of 99mTc-albumin 10 min after intravenous injection was used as an indicator of paracellular permeability of the BBB, its small but significant increase at the injury site indicating the level of persistent BBB disruption. The uptake of 125I-LIF by the injured lumbar spinal cord was significantly greater than that in the uninjured controls as well as that of 99mTc-albumin. Both excess unlabeled LIF and the blocking antibody against LIFRα significantly suppressed the increased entry of 125I-LIF without affecting that of 99mTc-albumin. Thus, the increased blood-to-spinal cord permeation of LIF was not solely explained by barrier disruption but involved LIFRα. This enhanced transport correlated with increased expression of LIFRα shown by immunofluorescent staining and Western blot. Therefore, LIFR at the BBB provides an important target for therapeutic intervention.