Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions

Servio H. Ramirez, János Haskó, Andrew Skuba, Shongshan Fan, Holly Dykstra, Ryan McCormick, Nancy Reichenbach, I. Krizbai, Anu Mahadevan, Ming Zhang, Ronald Tuma, Young Jin Son, Yuri Persidsky

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti-inflammatory effects. However, in this context, little is known about how selective activation of the cannabinoid type-2 receptor (CB2R) affects the activated state of the brain endothelium and blood- brain barrier (BBB) function. Using human brain tissues and primary human brain microvascular endothelial cells (BMVECs), we demonstrate that the CB2R is highly upregulated during inflammatory insult. We then examined whether the CB2R agonists could attenuate inflammatory responses at the BBB using a mouse model of LPS-induced encephalitis and highly selective CB2R agonists. Visualization by intravital microscopy revealed that administration of JWH133 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran] or a novel resorcinol-based compound, O-1966 (1-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-3-methyl-cyclohexanol), greatly attenuated leukocyte adhesion in surface pial vessels and in deep ascending corticalpostcapillary venules. BBB permeability assessments with small and largefluorescent tracers showedthat CB2R agonists were effective at preventing barrier leakiness after LPS administration. To determine whether the effects by CB2R agonists on barrier protection are not only due to the CB2R modulation of immune cell function, we tested the agonists in vitro with barrier-forming primary BMVECs. Remarkably, the addition of CB2R agonist increased transendothelial electrical resistance and increased the amount of tight junction protein present in membrane fractions. Furthermore, CB2R agonists decreased the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 surface expression in BMVECs exposed to various proinflammatory mediators. Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation.

Original languageEnglish
Pages (from-to)4004-4016
Number of pages13
JournalJournal of Neuroscience
Volume32
Issue number12
DOIs
Publication statusPublished - Mar 21 2012

Fingerprint

Cannabinoid Receptor Agonists
Cannabinoid Receptors
Blood-Brain Barrier
Cell Communication
Leukocytes
Endothelial Cells
Brain
Tight Junction Proteins
Pyrans
Venules
Vascular Cell Adhesion Molecule-1
Encephalitis
Intercellular Adhesion Molecule-1
Electric Impedance
Endothelium
Permeability
Anti-Inflammatory Agents
Pharmacology
Ligands
Membranes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. / Ramirez, Servio H.; Haskó, János; Skuba, Andrew; Fan, Shongshan; Dykstra, Holly; McCormick, Ryan; Reichenbach, Nancy; Krizbai, I.; Mahadevan, Anu; Zhang, Ming; Tuma, Ronald; Son, Young Jin; Persidsky, Yuri.

In: Journal of Neuroscience, Vol. 32, No. 12, 21.03.2012, p. 4004-4016.

Research output: Contribution to journalArticle

Ramirez, SH, Haskó, J, Skuba, A, Fan, S, Dykstra, H, McCormick, R, Reichenbach, N, Krizbai, I, Mahadevan, A, Zhang, M, Tuma, R, Son, YJ & Persidsky, Y 2012, 'Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions', Journal of Neuroscience, vol. 32, no. 12, pp. 4004-4016. https://doi.org/10.1523/JNEUROSCI.4628-11.2012
Ramirez, Servio H. ; Haskó, János ; Skuba, Andrew ; Fan, Shongshan ; Dykstra, Holly ; McCormick, Ryan ; Reichenbach, Nancy ; Krizbai, I. ; Mahadevan, Anu ; Zhang, Ming ; Tuma, Ronald ; Son, Young Jin ; Persidsky, Yuri. / Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 12. pp. 4004-4016.
@article{eeab6fa5a9bd4e6c94a0e16a74764f0a,
title = "Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions",
abstract = "Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti-inflammatory effects. However, in this context, little is known about how selective activation of the cannabinoid type-2 receptor (CB2R) affects the activated state of the brain endothelium and blood- brain barrier (BBB) function. Using human brain tissues and primary human brain microvascular endothelial cells (BMVECs), we demonstrate that the CB2R is highly upregulated during inflammatory insult. We then examined whether the CB2R agonists could attenuate inflammatory responses at the BBB using a mouse model of LPS-induced encephalitis and highly selective CB2R agonists. Visualization by intravital microscopy revealed that administration of JWH133 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran] or a novel resorcinol-based compound, O-1966 (1-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-3-methyl-cyclohexanol), greatly attenuated leukocyte adhesion in surface pial vessels and in deep ascending corticalpostcapillary venules. BBB permeability assessments with small and largefluorescent tracers showedthat CB2R agonists were effective at preventing barrier leakiness after LPS administration. To determine whether the effects by CB2R agonists on barrier protection are not only due to the CB2R modulation of immune cell function, we tested the agonists in vitro with barrier-forming primary BMVECs. Remarkably, the addition of CB2R agonist increased transendothelial electrical resistance and increased the amount of tight junction protein present in membrane fractions. Furthermore, CB2R agonists decreased the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 surface expression in BMVECs exposed to various proinflammatory mediators. Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation.",
author = "Ramirez, {Servio H.} and J{\'a}nos Hask{\'o} and Andrew Skuba and Shongshan Fan and Holly Dykstra and Ryan McCormick and Nancy Reichenbach and I. Krizbai and Anu Mahadevan and Ming Zhang and Ronald Tuma and Son, {Young Jin} and Yuri Persidsky",
year = "2012",
month = "3",
day = "21",
doi = "10.1523/JNEUROSCI.4628-11.2012",
language = "English",
volume = "32",
pages = "4004--4016",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "12",

}

TY - JOUR

T1 - Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions

AU - Ramirez, Servio H.

AU - Haskó, János

AU - Skuba, Andrew

AU - Fan, Shongshan

AU - Dykstra, Holly

AU - McCormick, Ryan

AU - Reichenbach, Nancy

AU - Krizbai, I.

AU - Mahadevan, Anu

AU - Zhang, Ming

AU - Tuma, Ronald

AU - Son, Young Jin

AU - Persidsky, Yuri

PY - 2012/3/21

Y1 - 2012/3/21

N2 - Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti-inflammatory effects. However, in this context, little is known about how selective activation of the cannabinoid type-2 receptor (CB2R) affects the activated state of the brain endothelium and blood- brain barrier (BBB) function. Using human brain tissues and primary human brain microvascular endothelial cells (BMVECs), we demonstrate that the CB2R is highly upregulated during inflammatory insult. We then examined whether the CB2R agonists could attenuate inflammatory responses at the BBB using a mouse model of LPS-induced encephalitis and highly selective CB2R agonists. Visualization by intravital microscopy revealed that administration of JWH133 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran] or a novel resorcinol-based compound, O-1966 (1-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-3-methyl-cyclohexanol), greatly attenuated leukocyte adhesion in surface pial vessels and in deep ascending corticalpostcapillary venules. BBB permeability assessments with small and largefluorescent tracers showedthat CB2R agonists were effective at preventing barrier leakiness after LPS administration. To determine whether the effects by CB2R agonists on barrier protection are not only due to the CB2R modulation of immune cell function, we tested the agonists in vitro with barrier-forming primary BMVECs. Remarkably, the addition of CB2R agonist increased transendothelial electrical resistance and increased the amount of tight junction protein present in membrane fractions. Furthermore, CB2R agonists decreased the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 surface expression in BMVECs exposed to various proinflammatory mediators. Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation.

AB - Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti-inflammatory effects. However, in this context, little is known about how selective activation of the cannabinoid type-2 receptor (CB2R) affects the activated state of the brain endothelium and blood- brain barrier (BBB) function. Using human brain tissues and primary human brain microvascular endothelial cells (BMVECs), we demonstrate that the CB2R is highly upregulated during inflammatory insult. We then examined whether the CB2R agonists could attenuate inflammatory responses at the BBB using a mouse model of LPS-induced encephalitis and highly selective CB2R agonists. Visualization by intravital microscopy revealed that administration of JWH133 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran] or a novel resorcinol-based compound, O-1966 (1-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-3-methyl-cyclohexanol), greatly attenuated leukocyte adhesion in surface pial vessels and in deep ascending corticalpostcapillary venules. BBB permeability assessments with small and largefluorescent tracers showedthat CB2R agonists were effective at preventing barrier leakiness after LPS administration. To determine whether the effects by CB2R agonists on barrier protection are not only due to the CB2R modulation of immune cell function, we tested the agonists in vitro with barrier-forming primary BMVECs. Remarkably, the addition of CB2R agonist increased transendothelial electrical resistance and increased the amount of tight junction protein present in membrane fractions. Furthermore, CB2R agonists decreased the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 surface expression in BMVECs exposed to various proinflammatory mediators. Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation.

UR - http://www.scopus.com/inward/record.url?scp=84863380403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863380403&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.4628-11.2012

DO - 10.1523/JNEUROSCI.4628-11.2012

M3 - Article

C2 - 22442067

AN - SCOPUS:84863380403

VL - 32

SP - 4004

EP - 4016

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 12

ER -