CD200‐CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation

Abstract

The endocannabinoid anandamide (AEA) is released by macrophages and microglia on pathological neuroinflammatory conditions such as multiple sclerosis (MS). CD200 is a membrane glycoprotein expressed in neurons that suppresses immune activity via its receptor (CD200R) mainly located in macrophages/microglia. CD200‐CD200R interactions contribute to the brain immune privileged status. In this study, we show that AEA protects neurons from microglia‐induced neurotoxicity via CD200‐CD200R interaction. AEA increases the expression of CD200R1 in LPS/IFN‐γ activated microglia through the activation of CB2 receptors. The neuroprotective effect of AEA disappears when microglial cells derive from CD200R1−/− mice. We also show that engagement of CD200R1 by CD200Fc decreased the production of the proinflammatory cytokines IL‐1β and IL‐6, but increased IL‐10 in activated microglia. In the chronic phases of Theiler's virus‐induced demyelinating disease (TMEV‐IDD) the expression of CD200 and CD200R1 was reduced in the spinal cord. AEA‐treated animals up‐regulated the expression of CD200 and CD200R1, restoring levels found in sham animals together with increased expression of IL‐10 and reduced expression of IL‐1β and IL‐6. Treated animals also improved their motor behavior. Because AEA up‐regulated the expression of CD200R1 in microglia, but failed to enhance CD200 in neurons we suggest that AEA‐induced up‐regulation of CD200 in TMEV‐IDD is likely due to IL‐10 as this cytokine increases CD200 in neurons. Our findings provide a new mechanism of action of AEA to limit immune response in the inflamed brain. © 2012 Wiley Periodicals, Inc.

Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55

“…Hippocampal neuronal cultures were prepared from mice embryos (embryonic day 17-18), as previously described (15). After the dissection, cortices were stripped of meningeal tissue and dissociated in PBS containing trypsin without EDTA (Thermo Fisher Scientific) and deoxyribonuclease I (1 mg/ml; Roche Diagnostics, Manheim, Germany) at 37˚C for 15 min.…”

Identification of prostamides, fatty acyl ethanolamines, and their biosynthetic precursors in rabbit cornea

“…Prostamides do not show potent interaction with prostanoid receptors, and studies using isolated feline iris cells have suggested the presence of prostamide-sensitive receptors different from the ones responding to PGs (22)(23)(24). The prostamide precursor A-EA has also been shown to exhibit neuroprotective and analgesic roles in infl ammation and pain models ( 25,26 ), Instrument control and data acquisition were performed using the MassLynx™ V4.0 software. For optimization of ESI/MS and ESI/MS/MS conditions, individual standards (10 ng/ l) were introduced into the spectrometer by direct infusion through a syringe pump (fl ow rate 10 l/min) through the HPLC solvent fl ow (rate 0.2 ml/min).…”

“…the tissue specifi c distribution of sn -1 docosahexanoyl species of PC ( 43 ). Although A-EA is considered a minor lipid species, representing only 1-10% of total FA-EA in human membranes under basal conditions, studies carried out in brain and nervous tissue indicate A-EA levels are increased in response to injury ( 44,45 ), and that A-EA participates as an antiinfl ammatory agent of the immune response ( 25,46 ). Few studies have examined the actions of A-EA per se in the cornea; however, it is a highly innervated tissue, and CB 1 receptors expressed on corneal sensory nerves stimulated by an agonist were found to support a role in contributing to antinociception in the anterior eye ( 47 ).…”

FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus

“…Theiler's virus (TMEV) induction of inflammatory processes is thought to be primarily mediated via TLR3 activation (So et al, 2006). In vitro data have demonstrated that anandamide downregulates proinflammatory cytokines IL-12, IL-17, TNFα and enhances IL-10 and IL-6 levels in TMEV-infected astrocytes (Molina-Holgado et al, 1997, 1998Correa et al, 2011;Hernangomez et al, 2012). Furthermore, PEA or FAAH inhibition attenuates microglial activation, the expression of pro-inflammatory cytokines and ameliorates motor symptoms in the TMEV-model of multiple sclerosis (Mestre et al, 2005;Ortega-Gutierrez et al, 2005;Loria et al, 2008;Loria et al, 2010;Correa et al, 2011;Hernangomez et al, 2012).…”