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Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain.

Publication Type:

Journal Article

Source:

J Neurosci, Volume 27, Issue 10, p.2596-605 (2007)

Keywords:

Animals, Antigens, CD11b, Antiviral Agents, Apoptosis, Brain, Brain Ischemia, Cell Proliferation, Cerebral Infarction, Cytokines, Cytoprotection, Galectin 3, Ganciclovir, Inflammation Mediators, Insulin-Like Growth Factor I, Macrophage Colony-Stimulating Factor, Male, Mice, Mice, Transgenic, Microglia, Mutation, Neurons, Simplexvirus, Thymidine Kinase, Tissue Distribution

Abstract:

<p>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 approximately 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.</p>

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