Transport of the Proinflammatory Chemokines C-C Motif Chemokine Ligand 2 (MCP-1) and C-C Motif Chemokine Ligand 5 (RANTES) across the Intact Mouse Blood-Brain Barrier Is Inhibited by Heparin and Eprodisate and Increased with Systemic Inflammation
U.S. Government work not protected by U.S. copyright..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:384 |
|---|---|
| Enthalten in: |
The Journal of pharmacology and experimental therapeutics - 384(2023), 1 vom: 28. Jan., Seite 205-223 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Quaranta, Daniel V [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 26.12.2022 Date Revised 10.02.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1124/jpet.122.001380 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM348243057 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM348243057 | ||
| 003 | DE-627 | ||
| 005 | 20231226035723.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1124/jpet.122.001380 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1160.xml |
| 035 | |a (DE-627)NLM348243057 | ||
| 035 | |a (NLM)36310035 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Quaranta, Daniel V |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Transport of the Proinflammatory Chemokines C-C Motif Chemokine Ligand 2 (MCP-1) and C-C Motif Chemokine Ligand 5 (RANTES) across the Intact Mouse Blood-Brain Barrier Is Inhibited by Heparin and Eprodisate and Increased with Systemic Inflammation |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.12.2022 | ||
| 500 | |a Date Revised 10.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a U.S. Government work not protected by U.S. copyright. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Iodine-125 |2 NLM | |
| 650 | 7 | |a GVO776611R |2 NLM | |
| 650 | 7 | |a eprodisate |2 NLM | |
| 650 | 7 | |a 6QFP76V7S7 |2 NLM | |
| 650 | 7 | |a Heparin |2 NLM | |
| 650 | 7 | |a 9005-49-6 |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Chemokines |2 NLM | |
| 650 | 7 | |a Receptors, Chemokine |2 NLM | |
| 650 | 7 | |a Heparitin Sulfate |2 NLM | |
| 650 | 7 | |a 9050-30-0 |2 NLM | |
| 700 | 1 | |a Weaver, Riley R |e verfasserin |4 aut | |
| 700 | 1 | |a Baumann, Kristen K |e verfasserin |4 aut | |
| 700 | 1 | |a Fujimoto, Takashi |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Lindsey M |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Hyung Chan |e verfasserin |4 aut | |
| 700 | 1 | |a Logsdon, Aric F |e verfasserin |4 aut | |
| 700 | 1 | |a Omer, Mohamed |e verfasserin |4 aut | |
| 700 | 1 | |a Reed, May J |e verfasserin |4 aut | |
| 700 | 1 | |a Banks, William A |e verfasserin |4 aut | |
| 700 | 1 | |a Erickson, Michelle A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of pharmacology and experimental therapeutics |d 1945 |g 384(2023), 1 vom: 28. Jan., Seite 205-223 |w (DE-627)NLM000006475 |x 1521-0103 |7 nnns |
| 773 | 1 | 8 | |g volume:384 |g year:2023 |g number:1 |g day:28 |g month:01 |g pages:205-223 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1124/jpet.122.001380 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 384 |j 2023 |e 1 |b 28 |c 01 |h 205-223 | ||