CD200-CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation.
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 CB(2) 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.
Department of Functional and Systems Neurobiology, Neuroimmunology Group, Instituto Cajal, CSIC, Madrid, Spain.
Miriam
M
Hernangómez
Leyre
L
Mestre
Fernando G
FG
Correa
Frida
F
Loría
Miriam
M
Mecha
Paula M
PM
Iñigo
Fabian
F
Docagne
Richard O
RO
Williams
José
J
Borrell
Carmen
C
Guaza
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D064446:Orexin Receptors; D053284:Polyunsaturated Alkamides / Q000494:pharmacology / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000378:metabolism*
D015703:Antigens, CD; D000954:Antigens, Surface; D001095:Arachidonic Acids; C501103:Cd200r1 protein, mouse; D063388:Endocannabinoids; D053583:Interleukin-1beta; D015850:Interleukin-6; D018696:Neuroprotective Agents; D064446:Orexin Receptors; D053284:Polyunsaturated Alkamides; D011956:Receptors, Cell Surface; C042739:antigens, CD200; C078814:anandamide