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The Journal of Neuroscience, November 7, 2007, 27(45):12396-12406; doi:10.1523/JNEUROSCI.3016-07.2007

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Cellular/Molecular
Expression of CCR2 in Both Resident and Bone Marrow-Derived Microglia Plays a Critical Role in Neuropathic Pain

Ji Zhang,¹ Xiang Qun Shi,¹ Stefania Echeverry,¹ Jeffrey S. Mogil,² Yves De Koninck,¹ and Serge Rivest³

¹Unité de Neurobiologie Cellulaire, Centre de Recherche Université Laval Robert-Giffard, Québec, Québec, Canada G1J 2G3, ²Department of Psychology and The Alan Edwards Centre for Research on Pain, McGill University, Montreal, Québec, Canada H3A 2T5, and ³Laboratoire d'endocrinologie Moléculaire et Oncologique, Centre de Recherche du Centre Hospitalier de l'Université Laval, Québec, Québec, Canada G1V 4G2

Correspondence should be addressed to Dr. Ji Zhang at her present address: The Alan Edwards Centre for Research on Pain, McGill University, 740, Dr. Penfield Avenue, Suite 3200C, Montreal, Québec, Canada H3A 2B2. Email: ji.zhang{at}mcgill.ca

Neuropathic pain resulting from damage to or dysfunction of peripheral nerves is not well understood and difficult to treat. Although CNS hyperexcitability is a critical component, recent findings challenge the neuron-centric view of neuropathic pain etiology and pathology. Indeed, glial cells were shown to play an active role in the initiation and maintenance of pain hypersensitivity. However, the origins of these cells and the triggers that induce their activation have yet to be elucidated. Here we show that, after peripheral nerve injury induced by a partial ligation on the sciatic nerve, in addition to activation of microglia resident to the CNS, hematogenous macrophage/monocyte infiltrate the spinal cord, proliferate, and differentiate into microglia. Signaling from chemokine monocyte chemoattractant protein-1 (MCP-1, CCL2) to its receptor CCR2 is critical in the spinal microglial activation. Indeed, intrathecal injection of MCP-1 caused activation of microglia in wild-type but not in CCR2-deficient mice. Furthermore, treatment with an MCP-1 neutralizing antibody prevented bone marrow-derived microglia (BMDM) infiltration into the spinal cord after nerve injury. In addition, using selective knock-out of CCR2 in resident microglia or BMDM, we found that, although total CCR2 knock-out mice did not develop microglial activation or mechanical allodynia, CCR2 expression in either resident microglia or BMDM is sufficient for the development of mechanical allodynia. Thus, to effectively relieve neuropathic pain, both CNS resident microglia and blood-borne macrophages need to be targeted. These findings also open the door for a novel therapeutic strategy: to take advantage of the natural ability of bone marrow-derived cells to infiltrate selectively affected CNS regions by using these cells as vehicle for targeted drug delivery to inhibit hypersensitivity and chronic pain.

Key words: nerve injury; leukocyte infiltration; allodynia; spinal cord; chemokine; glial activation

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Received May 9, 2007; revised Sept. 17, 2007; accepted Sept. 18, 2007.

Correspondence should be addressed to Dr. Ji Zhang at her present address: The Alan Edwards Centre for Research on Pain, McGill University, 740, Dr. Penfield Avenue, Suite 3200C, Montreal, Québec, Canada H3A 2B2. Email: ji.zhang{at}mcgill.ca

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