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

J Neurosci. 2007 Mar 7;27(10):2596-605. doi: 10.1523/JNEUROSCI.5360-06.2007.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Apoptosis
  • Brain / metabolism
  • Brain / pathology*
  • Brain Ischemia / pathology*
  • CD11b Antigen / genetics
  • Cell Proliferation* / drug effects
  • Cerebral Infarction / pathology
  • Cytokines / metabolism
  • Cytoprotection
  • Galectin 3 / metabolism
  • Ganciclovir / pharmacology
  • Inflammation Mediators / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Male
  • Mice
  • Mice, Transgenic / virology
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology*
  • Mutation
  • Neurons / pathology
  • Simplexvirus / genetics
  • Thymidine Kinase / genetics
  • Tissue Distribution


  • Antiviral Agents
  • CD11b Antigen
  • Cytokines
  • Galectin 3
  • Inflammation Mediators
  • Insulin-Like Growth Factor I
  • Macrophage Colony-Stimulating Factor
  • Thymidine Kinase
  • Ganciclovir