Blood-brain barrier chemokine transporters as novel targets for neuroinflammation therapy

Overview

This research program identifies and validates a novel therapeutic target for neuroinflammation: heparan sulfate proteoglycans (HSPGs) on the luminal glycocalyx of brain endothelial cells, which act as transporters that shuttle chemokines such as CCL2, CCL5, and CCL11 from the bloodstream into the brain. Published and preliminary work from the University of Washington shows that systemic inflammation can increase CCL2 and CCL5 transport rates by 10–20 fold, approaching glucose-level kinetics, even without disrupting blood-brain barrier (BBB) integrity. Because these chemokines drive neuroinflammatory and neuropsychiatric pathophysiology, blocking their HSPG-dependent transport represents a promising new strategy for treating conditions ranging from sickness behavior to depression-like cognitive impairment.

Technical specifications

Key scientific findings and capabilities:

• Demonstrated in vivo that CCL2 and CCL5 cross the intact mouse BBB via heparan sulfate–dependent mechanisms, using highly sensitive in-house radiotracer assays
• Showed that low-dose lipopolysaccharide (LPS) substantially increases brain uptake of CCL2 and CCL5 without causing BBB leakage
• Established a robust iPSC-derived human in vitro BBB model that recapitulates heparan sulfate–dependent CCL2 transport, enabling translational drug screening
• Identified specific HSPG candidates (syndecans and glypicans) as candidate transporters for future competitive inhibition studies
• Validated an anti-CCL2 blocking antibody approach that inhibits blood-to-brain CCL2 transport while sparing centrally produced CCL2, allowing mechanistic dissection of peripheral chemokine contributions to neuroinflammation and depressive-like behavior

Technology readiness level

The program is at an early-to-mid preclinical stage. Target identification and in vitro/in vivo proof-of-concept transport data have been completed and published. Future validation (Years 1–2) will identify the specific syndecan and glypican transporters responsible for CCL2 transport and quantify the contribution of BBB chemokine transport to neuroinflammation and cognitive impairment in LPS-treated mice using blocking antibodies and behavioral endpoints. The work is positioned to advance toward therapeutic candidate development and partnership with industry for neuroinflammatory and neuropsychiatric drug discovery.