Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells.
Increased blood levels of the eotaxin chemokine C-C motif ligand 11 (CCL11) in aging were recently shown to negatively regulate adult hippocampal neurogenesis. How circulating CCL11 could affect the central nervous system (CNS) is not clear, but one possibility is that it can cross the blood-brain barrier (BBB). Here, we show that CCL11 undergoes bidirectional transport across the BBB. Transport of CCL11 from blood into whole brain (influx) showed biphasic kinetics, with a slow phase preceding a rapid phase of uptake. We found that the slow phase was explained by binding of CCL11 to cellular components in blood, whereas the rapid uptake phase was mediated by direct interactions with the BBB. CCL11, even at high doses, did not cause BBB disruption. All brain regions except striatum showed a delayed rapid-uptake phase. Striatum had only an early rapid-uptake phase, which was the fastest of any brain region. We also observed a slow but saturable transport system for CCL11 from brain to blood. C-C motif ligand 3 (CCR3), an important receptor for CCL11, did not facilitate CCL11 transport across the BBB, although high concentrations of a CCR3 inhibitor increased brain uptake without causing BBB disruption. Our results indicate that CCL11 in the circulation can access many regions of the brain outside of the neurogenic niche via transport across the BBB. This suggests that blood-borne CCL11 may have important physiologic functions in the CNS and implicates the BBB as an important regulator of physiologic versus pathologic effects of this chemokine.
University of Pennsylvania, Department of Pathology, School of Dental Medicine, Philadelphia, Pennsylvania (M.A.E.); Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (M.A.E., Y.M., J.B.O., W.A.B.); Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Seattle, Washington (M.A.E., Y.M., J.B.O., W.A.B.); Department of Chemistry, University of Kentucky, Lexington, Kentucky (J.B.O.); and Department of Neurosurgery, University of Nagasaki, Nagasaki, Japan (Y.M.).
Michelle A
MA
Erickson
Yoichi
Y
Morofuji
Joshua B
JB
Owen
William A
WA
Banks
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D061251:Primary Cell Culture; D012044:Regression Analysis; D014018:Tissue Distribution
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D007457:Iodine Radioisotopes