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

Abstract

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.

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  • Authors+Show Affiliations

    ,

    Department of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l'Université Laval, Quebec, Canada G1V 4G2.

    , , ,

    Source

    MeSH

    Animals
    Antiviral Agents
    Apoptosis
    Brain
    Brain Ischemia
    CD11b Antigen
    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

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17344397

    Citation

    Lalancette-Hébert, Mélanie, et al. "Selective Ablation of Proliferating Microglial Cells Exacerbates Ischemic Injury in the Brain." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 27, no. 10, 2007, pp. 2596-605.
    Lalancette-Hébert M, Gowing G, Simard A, et al. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007;27(10):2596-605.
    Lalancette-Hébert, M., Gowing, G., Simard, A., Weng, Y. C., & Kriz, J. (2007). Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 27(10), pp. 2596-605.
    Lalancette-Hébert M, et al. Selective Ablation of Proliferating Microglial Cells Exacerbates Ischemic Injury in the Brain. J Neurosci. 2007 Mar 7;27(10):2596-605. PubMed PMID: 17344397.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. AU - Lalancette-Hébert,Mélanie, AU - Gowing,Geneviève, AU - Simard,Alain, AU - Weng,Yuan Cheng, AU - Kriz,Jasna, PY - 2007/3/9/pubmed PY - 2007/4/10/medline PY - 2007/3/9/entrez SP - 2596 EP - 605 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 27 IS - 10 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/17344397/Selective_ablation_of_proliferating_microglial_cells_exacerbates_ischemic_injury_in_the_brain_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17344397 DB - PRIME DP - Unbound Medicine ER -