Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

Abstract

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.

CCL11 (Eotaxin-1) Levels Predict Long-Term Functional Outcomes in Patients Following Ischemic Stroke

“…Previous pre-clinical experiments have shown that circulating CCL11 is capable of crossing the blood brain barrier and results in decreased neurogenesis in mice [6,17]. In primary cell lines obtained from mice, treatment with exogenous CCL11 increases microglial migration and induces the production of microglial reactive oxygen species, directly contributing to neuronal death in co-culture systems [18].…”

CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia

“…Systemic inflammation can induce CCL11 production in various cell types outside the CNS, such as leukocytes, fibroblasts, chondrocytes, and endothelial cells . A recent study described a system for rapid transport of CCL11 across the blood-brain barrier (Erickson et al, 2014), suggest-ing that blood-borne CCL11 may also affect microglia and accelerate the progression of various neurological disorders.…”

Cytokine alterations and cognitive impairment in major depressive disorder: From putative mechanisms to novel treatment targets

“…Indeed, eotaxin has been found to facilitate cognitive decline during aging by direct inhibition of adult hippocampal neurogenesis (Villeda et al, 2011). Interestingly, eotaxin undergoes a bidirectional transport through BBB that is mediated by binding to the blood cellular components in the slow phase and direct interactions with BBB in the rapid phase (Erickson et al, 2014). In the study by Goldsmith et al (2016a), higher levels of Monocyte Chemoattractant Protein-1 (MCP-1) were associated with worse performance in tests measuring processing speed, motor speed and lateralized coordination.…”