Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.
The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity. We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB(2) receptor.
Maresz
Katarzyna
K
BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, Wisconsin 53226, USA.
Pryce
Gareth
G
Ponomarev
Eugene D
ED
Marsicano
Giovanni
G
Croxford
J Ludovic
JL
Shriver
Leah P
LP
Ledent
Catherine
C
Cheng
Xiaodong
X
Carrier
Erica J
EJ
Mann
Monica K
MK
Giovannoni
Gavin
G
Pertwee
Roger G
RG
Yamamura
Takashi
T
Buckley
Nancy E
NE
Hillard
Cecilia J
CJ
Lutz
Beat
B
Baker
David
D
Dittel
Bonnie N
BN
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D049109:Cell Proliferation; D002490:Central Nervous System / Q000378:metabolism*; D017931:DNA Primers; D004660:Encephalitis / Q000209:etiology / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
C469526:Cnr2 protein, rat; D017931:DNA Primers; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2