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The Journal of Neuroscience, March 7, 2007, 27(10):2596-2605; doi:10.1523/JNEUROSCI.5360-06.2007
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Neurobiology of Disease
Selective Ablation of Proliferating Microglial Cells Exacerbates Ischemic Injury in the Brain
Mélanie Lalancette-Hébert, Geneviève Gowing, Alain Simard, Yuan Cheng Weng, andJasna Kriz Department of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l'Université Laval, Quebec, Canada G1V 4G2
Correspondence should be addressed to Dr. Jasna Kriz, Assistant Professor, Faculty of Medicine, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), T3-67, Université Laval, 2705 boulevard Laurier, Québec, Canada G1V 4G2. Email: Jasna.Kriz{at}crchul.ulaval.ca
Here we report in vivo evidence of a neuroprotective role of proliferating microglial cells in cerebral ischemia. Using transgenic mice expressing a mutant thymidine kinase form of herpes simplex virus driven by myeloid-specific CD11b promoter and ganciclovir treatment as a tool, we selectively ablated proliferating (Mac-2 positive) microglia after transient middle cerebral artery occlusion. The series of experiments using green fluorescent protein-chimeric mice demonstrated that within the first 72 h after ischemic injury, the Mac-2 marker [unlike Iba1 (ionized calcium-binding adapter molecule 1)] was preferentially expressed by the resident microglia. Selective ablation of proliferating resident microglia was associated with a marked alteration in the temporal dynamics of proinflammatory cytokine expression, a significant increase in the size of infarction associated with a 2.7-fold increase in the number of apoptotic cells, predominantly neurons, and a 1.8-fold decrease in the levels of IGF-1. A double-immunofluorescence analysis revealed a
100% colocalization between IGF-1 positive cells and Mac-2, a marker of activated/proliferating resident microglia. Conversely, stimulation of microglial proliferation after cerebral ischemia by M-CSF (macrophage colony stimulating factor) resulted in a 1.9-fold increase in IGF-1 levels and a significant increase of Mac2+cells. Our findings suggest that a postischemic proliferation of the resident microglial cells may serve as an important modulator of a brain inflammatory response. More importantly, our results revealed a marked neuroprotective potential of proliferating microglia serving as an endogenous pool of neurotrophic molecules such as IGF-1, which may open new therapeutic avenues in the treatment of stroke and other neurological disorders.
Key words: glia; growth factor; ischemia; mice; neuroinflammation; neuroprotection; transgenic
Received Sept. 5, 2006; revised Jan. 24, 2007; accepted Jan. 27, 2007.
Correspondence should be addressed to Dr. Jasna Kriz, Assistant Professor, Faculty of Medicine, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), T3-67, Université Laval, 2705 boulevard Laurier, Québec, Canada G1V 4G2. Email: Jasna.Kriz{at}crchul.ulaval.ca
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