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Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells

Abstract

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 CB1 and CB2 cannabinoid receptors in regulating CNS autoimmunity. We found that CB1 receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB2 receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB2-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 CB2 receptor.

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Figure 1: EAE is suppressed by THC in wild-type mice and is enhanced when induced with CB2−/− T cells, which, unlike CB1−/− T cells, are not responsive to the CB2 receptor agonist JWH-133.
Figure 2: Increased number of CB2−/− encephalitogenic T cells as compared to wild-type T cells in the CNS is correlated with increased cell proliferation, decreased apoptosis and increased cytokine production.

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Acknowledgements

We thank S. Morris-Islo for assistance with the mice and Roche Palo Alto for providing CB1−/− mice. This work was supported in part by US National Institutes of Health grants R01 NS046662 (B.N.D.), R01 NS041314 (C.J.H.) and DA09155 (C.J.H.), the BloodCenter Research Foundation (B.N.D.), the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society and Aims2cure. J.L.C. is a Research Fellow of the Japan Society for the Promotion of Science (P03581). The authors thank the National Institute on Drug Abuse chemical supply program for donating chemicals for this study.

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K.M. helped design and performed all of the experiments depicted in Figures 1 and 2 (except Fig. 1a) and Table 2, with technical advice and assistance from E.D.P., X.C., E.J.C. and M.K.M in B.N.D.'s laboratory. L.P.S. performed the immunohistology in B.N.D.'s laboratory. G.P. bred and screened conditional knockouts and designed and performed EAE experiments. B.L. supervised G.M. in the production of the conditional CB1 floxed mice, obtained the funding and provided the techniques for screening the mice. J.L.C. performed EAE experiments in T.Y. and D.B.'s laboratories, and performed supportive experiments of cannabinoids in EAE, cytokine analysis and T-cell responses in T.Y.'s laboratory. C.L. produced the generalized CB1 receptor knockout mouse and provided techniques for their screening. G.G. assisted with intellectual direction and experimental design and obtained funding for the studies and personnel costs. R.G.P. is a cannabinoid pharmacologist who collaborated on the project since its initiation in 1989 providing intellectual input for experimental design, drug selection and obtained compounds for the project. T.Y. obtained funding for the project. N.E.B. provided the CB2−/− mice. C.J.H. helped with experimental design and writing of the manuscript; her laboratory backcrossed the CB1−/− mice onto the ICR background. D.B. bred and screened conditional mice, initiated the project and performed and designed EAE experiments (Fig. 1a and Table 1). B.N.D. supervised K.M. and colleagues and helped with experimental design. D.B. and B.N.D. secured funding and permission to undertake the study and helped write the manuscript.

Corresponding author

Correspondence to Bonnie N Dittel.

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Competing interests

D.B. is the founding member of Canbex, a company that aims to produce pharmaceutical cannabinoids for the treatment of multiple sclerosis. R.G.P. is Director of Pharmacology for GW Pharmaceuticals, which produces cannabis-based medicines.

Supplementary information

Supplementary Table 1

Comparison of EAE clinical disease parameters induced by active immunization in WT and CB2−/− mice. (PDF 42 kb)

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Maresz, K., Pryce, G., Ponomarev, E. et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med 13, 492–497 (2007). https://doi.org/10.1038/nm1561

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