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Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain.
J Neurosci 2007; 27(10):2596-605JN

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.

Authors+Show Affiliations

Department of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l'Université Laval, Quebec, Canada G1V 4G2.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -