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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 (CB(2)) dampens immune activation. Here, we show that the genetic deletion of CB(2) receptors in a slowly progressing HD mouse model accelerates the onset of motor deficits and increases their severity. Treatment of mice with a CB(2) receptor agonist extends life span and suppresses motor deficits, synapse loss, and CNS inflammation, while a peripherally restricted CB(2) receptor antagonist blocks these effects. CB(2) 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 CB(2) 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.

Cannabinoid Receptor 2 Signaling in Peripheral Immune Cells Modulates Disease Onset and Severity in Mouse Models of Huntington's Disease