Cannabinoid Receptor 2 Signaling in Peripheral Immune Cells Modulates Disease Onset and Severity in Mouse Models of Huntington's Disease
- Jill Bouchard1,2,
- Jennifer Truong2,
- Kristofer Bouchard3,4,5,
- Diana Dunkelberger2,
- Sandrine Desrayaud6,
- Saliha Moussaoui6,
- Sarah J. Tabrizi7,
- Nephi Stella8, and
- Paul J. Muchowski1,2,9,10,11
- 1Neuroscience Program, University of California San Francisco, California 94158,
- 2Gladstone Institute of Neurological Disease, San Francisco, California 94158,
- 3Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94158,
- 4Center for Integrative Neuroscience, San Francisco, California 94158,
- 5Center for Neural Engineering and Prosthesis, San Francisco-Berkeley, California 94158,
- 6Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland,
- 7Department of Neurodegenerative Disease, UCL Institute of Neurology, London WCIN 3BG, United Kingdom,
- 8Department of Pharmacology and Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195-7280,
- 9Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158,
- 10Department of Neurology, University of California, San Francisco, California 94158, and
- 11Taube-Koret Center for Huntington's Disease Research, San Francisco, California 94158
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Author contributions: J.B., S.J.T., N.S., and P.J.M. designed research; J.B., J.T., D.D., S.D., and S.M. performed research; J.B., J.T., K.B., D.D., S.D., S.M., S.J.T., and P.J.M. analyzed data; J.B., N.S., and P.J.M. wrote the paper.
Abstract
Peripheral immune cells and brain microglia exhibit an activated phenotype in premanifest Huntington's disease (HD) patients that persists chronically and correlates with clinical measures of neurodegeneration. However, whether activation of the immune system contributes to neurodegeneration in HD, or is a consequence thereof, remains unclear. Signaling through cannabinoid receptor 2 (CB2) dampens immune activation. Here, we show that the genetic deletion of CB2 receptors in a slowly progressing HD mouse model accelerates the onset of motor deficits and increases their severity. Treatment of mice with a CB2 receptor agonist extends life span and suppresses motor deficits, synapse loss, and CNS inflammation, while a peripherally restricted CB2 receptor antagonist blocks these effects. CB2 receptors regulate blood interleukin-6 (IL-6) levels, and IL-6 neutralizing antibodies partially rescue motor deficits and weight loss in HD mice. These findings support a causal link between CB2 receptor signaling in peripheral immune cells and the onset and severity of neurodegeneration in HD, and they provide a novel therapeutic approach to treat HD.
- Received August 21, 2012.
- Revision received October 9, 2012.
- Accepted October 31, 2012.
- Copyright © 2012 the authors 0270-6474/12/3218259-10$15.00/0
