One important function of the vascular blood-brain barrier (BBB) is to facilitate neuroimmune communication. The BBB fulfills this function, in part, through its ability to transport
cytokines and
chemokines. C-C motif
chemokine receptor 2 (CCL2) (MCP-1) and C-C motif
chemokine receptor 5 (CCL5) (
RANTES) are proinflammatory
chemokines that mediate neuroimmune responses to acute insults and aspects of
brain injury and
neurodegenerative diseases; however, a blood-to-brain transport system has not been evaluated for either
chemokine in vivo. Therefore, we determined whether CCL2 and CCL5 in blood can cross the intact BBB and enter the brain. Using CD-1 mice, we found that 125I-labeled CCL2 and CCL5 crossed the BBB and entered the brain parenchyma. We next aimed to identify the mechanisms of 125I-CCL2 and 125I-CCL5 transport in an in situ brain perfusion model. We found that both
heparin and
eprodisate inhibited brain uptake of 125I-CCL2 and 125I-CCL5 in situ, whereas antagonists of their
receptors, CCR2 or CCR5, respectively, did not, suggesting that heparan
sulfates at the endothelial surface mediate BBB transport. Finally, we showed that CCL2 and CCL5 transport across the BBB increased following a single injection of 0.3 mg/kg
lipopolysaccharide. These data demonstrate that CCL2 and CCL5 in the brain can derive, in part, from the circulation, especially during systemic
inflammation. Further, binding to the BBB-associated
heparan sulfate is a mechanism by which both
chemokines can cross the intact BBB, highlighting a novel therapeutic target for treating
neuroinflammation. SIGNIFICANCE STATEMENT: Our work demonstrates that C-C motif
chemokine ligand 2 (CCL2) and C-C motif
chemokine ligand 5 (CCL5) can cross the intact blood-brain barrier and that transport is robustly increased during
inflammation. These data suggest that circulating CCL2 and CCL5 can contribute to brain levels of each
chemokine. We further show that the transport of both
chemokines is inhibited by
heparin and
eprodisate, suggesting that CCL2/CCL5-
heparan sulfate interactions could be therapeutically targeted to limit accumulation of these
chemokines in the brain.