Transport of the Chemokines CCL5 and CCL2 Across the Mouse Blood‐Brain Barrier under Physiological and Inflammatory Conditions

CCL5 趋化因子 神经炎症 血脑屏障 体内 化学 脂多糖 细胞生物学 免疫学 背景(考古学) 炎症 生物 体外 神经科学 中枢神经系统 生物化学 细胞毒性T细胞 生物技术 白细胞介素2受体 古生物学
作者
Daniel Quaranta,Michelle A. Erickson,Riley R Weaver,William A. Banks
出处
期刊:The FASEB Journal [Wiley]
卷期号:35 (S1)
标识
DOI:10.1096/fasebj.2021.35.s1.03909
摘要

Chemokines are important regulators of neuroinflammation and interact with brain endothelial cells that comprise the blood-brain barrier (BBB) to modulate their function and promote their interactions with leukocytes. Chemokines can also cross the intact BBB, which may contribute to their functions in the brain, but interactions of chemokines with the BBB in vivo are understudied. Here, we show that the chemokines C-C motif ligand 2 (CCL2) and C-C motif ligand 5 (CCL5), which have been well-studied in context of their neuroinflammatory functions, are amenable to labeling with 125I. This affords highly sensitive and quantitative detection of CCL2 and CCL5 in vivo, and allows for rapid assessment of the distribution of circulating chemokines. Multiple-time regression analysis was used to characterize chemokine transport across the mouse BBB. In untreated mice, we evaluated the brain uptake of CCL2 and CCL5 and characterized saturability of uptake and endothelial binding vs. transport. We then determined whether CCL2 and CCL5 interactions with the BBB are altered in mice treated with three doses of 3mg/kg lipopolysaccharide. Our results indicate that in addition to endothelial binding at the glycocalyx, there is uptake of both CCL5 and CCL2 into the mouse brain parenchyma. We found no significant difference in the rate of chemokine uptake in mice treated with LPS versus untreated mice. However, the 125I counts per minute (CPM) was significantly higher in the brains of LPS mice versus untreated mice brains, indicating that more radio-labelled chemokine had entered the brain after LPS-induced inflammation. In conclusion, we have found that chemokines interact with the intact BBB, and alterations in theses interactions with inflammation can be detected in vivo. As a future direction, this method can be utilized to evaluate pharmacological approaches to inhibiting BBB/chemokine interactions, which may protect against harmful neuroinflammation during neurological disease.

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