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The Journal of Neuroscience, August 27, 2003, 23(21):7922-7930

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Chemokine Expression by Glial Cells Directs Leukocytes to Sites of Axonal Injury in the CNS

Alicia A. Babcock,¹ William A. Kuziel,² Serge Rivest,³ and Trevor Owens¹

¹Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec Canada H3A 2B4, ²Institute of Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, and ³Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center and Department of Anatomy and Physiology, Laval University, Quebec, Canada G1V 4G2

Innate responses in the CNS are critical to first line defense against infection and injury. Leukocytes migrate to inflammatory sites in response to chemokines. We studied leukocyte migration and glial chemokine expression within the denervated hippocampus in response to axonal injury caused by entorhinodentate lesions. A population of Mac1/CD11b+ CD45^high macrophages (distinct from CD45^low microglia) was specifically detected within the lesion-reactive hippocampus by 12 hr after injury. Significant infiltration by CD3+ T cells did not occur in the denervated hippocampus until 24 hr after axotomy. A broad spectrum of chemokines [RANTES/CCL5, monocyte chemoattractant protein (MCP)-1/CCL2, interferon inducible protein (IP)-10/CXCL10, macrophage inflammatory protein (MIP)-1/CCL3, MIP-1/CCL4, and MIP-2/CXCL2] was induced at this time. RANTES/CCL5 was not significantly elevated until 24 hr after axotomy, whereas MCP-1/CCL2 was significantly induced before leukocyte infiltration occurred. Neither T cells nor macrophages infiltrated the denervated hippocampus of CCR2-deficient mice, arguing for a critical role for the CCR2 ligand MCP-1/CCL2 in leukocyte migration. Both T cells and macrophages infiltrated CCR5-deficient hippocampi, showing that CCR5 ligands (including RANTES/CCL5) are not critical to this response. In situ hybridization combined with immunohistochemistry for ionized binding calcium adapter molecule (iba)1 or glial fibrillary acidic protein (GFAP) identified iba1+ microglia and GFAP+ astrocytes as major sources of MCP-1/CCL2 within the lesion-reactive hippocampus. We conclude that leukocyte responses to CNS axonal injury are directed via innate glial production of chemokines.

Key words: chemokines; CCR2; CCR5; hippocampus; axotomy; microglia; astrocytes; macrophages; T cells; flow cytometry; in situ hybridization; RT-PCR; RNase protection

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Received March 26, 2003; revised July 7, 2003; accepted July 10, 2003.

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