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J. Biol. Chem., Vol. 283, Issue 19, 13320-13329, May 9, 2008

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The CB₂ Cannabinoid Receptor Controls Myeloid Progenitor Trafficking

INVOLVEMENT IN THE PATHOGENESIS OF AN ANIMAL MODEL OF MULTIPLE SCLEROSIS^*

Javier Palazuelos¹, Nathalie Davoust², Boris Julien³, Eric Hatterer, Tania Aguado⁴, Raphael Mechoulam^¶, Cristina Benito^||, Julian Romero^||, Augusto Silva^**, Manuel Guzmán, Serge Nataf⁵, and Ismael Galve-Roperh⁵⁶

From the Department of Biochemistry and Molecular Biology I, School of Biology, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Complutense University, 28040 Madrid, Spain, the INSERM U433, Institut Féderatif Recherche (IFR) des Neurosciences de Lyon, FacultédeMédecine Laënnec, 69372 Lyon, France, the ^¶Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University, 91120 Jerusalem, Israel, the ^||Laboratorio de Apoyo a la Investigación, Fundación Hospital Alcorcón, 28922 Madrid, Spain, and the ^**Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid,Spain

Cannabinoids are potential agents for the development of therapeutic strategies against multiple sclerosis. Here we analyzed the role of the peripheral CB₂ cannabinoid receptor in the control of myeloid progenitor cell trafficking toward the inflamed spinal cord and their contribution to microglial activation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). CB₂ receptor knock-out mice showed an exacerbated clinical score of the disease when compared with their wild-type littermates, and this occurred in concert with extended axonal loss, T-lymphocyte (CD4⁺) infiltration, and microglial (CD11b⁺) activation. Immature bone marrow-derived CD34⁺ myeloid progenitor cells, which play a role in neuroinflammatory pathologies, were shown to express CB₂ receptors and to be abundantly recruited toward the spinal cords of CB₂ knock-out EAE mice. Bone marrow-derived cell transfer experiments further evidenced the increased contribution of these cells to microglial replenishment in the spinal cords of CB₂-deficient animals. In line with these observations, selective pharmacological CB₂ activation markedly reduced EAE symptoms, axonal loss, and microglial activation. CB₂ receptor manipulation altered the expression pattern of different chemokines (CCL2, CCL3, CCL5) and their receptors (CCR1, CCR2), thus providing a mechanistic explanation for its role in myeloid progenitor recruitment during neuroinflammation. These findings demonstrate the protective role of CB₂ receptors in EAE pathology; provide evidence for a new site of CB₂ receptor action, namely the targeting of myeloid progenitor trafficking and its contribution to microglial activation; and support the potential use of non-psychoactive CB₂ agonists in therapeutic strategies for multiple sclerosis and other neuroinflammatory disorders.

Received for publication, September 24, 2007 , and in revised form, February 11, 2008.

^* This work was supported by grants from the Picasso Program (Grant HF2005-0017), Comunidad Autónoma de Madrid (Grants S-SAL/0261/2006 and 950344), Santander Complutense (Grant PR27/05-13988), Fundación de Investigación Médica Mutua Madrileña Automovilística, Ministerio de Educacion y Ciencia (Grants SAF2004/00237), the French Embassy in Spain, and Association pour la Recherche sur la Sclerose en Plaques. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

¹ Supported by the Ministerio de Educación y Ciencia (Formación de Personal Investigador program; Spain).

² Present address: INSERM U851, Universite de Lyon, 69365 Lyon Cedex 07, France.

³ Supported by the Fondation pour Recherche Medicale (France).

⁴ Supported by the Comunidad Autónoma de Madrid (Spain).

⁵ Both authors contributed equally to this work.

⁶ To whom correspondence should be addressed. Tel.: 34-913944668; Fax: 34-913944672; E-mail: igr{at}quim.ucm.es.

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