Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation.
BACKGROUND
Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.


RESULTS
JWH015 (a CBR2 agonist) increased MKP-1 and MKP-3 expression, which in turn reduced p-ERK1/2 in LPS-stimulated primary microglia. These effects resulted in a significant reduction of tumor necrosis factor-alpha (TNF) expression and microglial migration. We confirmed the causative link of these findings by using MKP inhibitors. We found that the selective inhibition of MKP-1 by Ro-31-8220 and PSI2106, did not affect p-ERK expression in LPS+JWH015-treated microglia. However, the inhibition of both MKP-1 and MKP-3 by triptolide induced an increase in p-ERK expression and in microglial migration using LPS+JWH015-treated microglia.


CONCLUSIONS
Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.
Romero-Sandoval
Edgar Alfonso
EA
Department of Anesthesiology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire 03756-1000, USA. edgar.a.romero-sandoval@dartmouth.edu
Horvath
Ryan
R
Landry
Russell P
RP
DeLeo
Joyce A
JA
D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000517:prevention & control; D017628:Microglia / Q000166:cytology*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
C469526:Cnr2 protein, rat; D043885:Receptor, Cannabinoid, CB2; D048049:Extracellular Signal-Regulated MAP Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054638:Dual Specificity Phosphatase 1; D054642:Dual Specificity Phosphatase 6