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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+ CD45high
macrophages (distinct from CD45low 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
Received March 26, 2003;
revised July 7, 2003;
accepted July 10, 2003.
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