Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain.
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.
Lalancette-Hébert
Mélanie
M
Department of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l'Université Laval, Quebec, Canada G1V 4G2.
Gowing
Geneviève
G
Simard
Alain
A
Weng
Yuan Cheng
YC
Kriz
Jasna
J
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D039481:CD11b Antigen / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002544:Cerebral Infarction / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D037502:Galectin 3 / Q000378:metabolism; D015774:Ganciclovir / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000821:virology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D009474:Neurons / Q000473:pathology; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D014018:Tissue Distribution
D000998:Antiviral Agents; D039481:CD11b Antigen; D016207:Cytokines; D037502:Galectin 3; D018836:Inflammation Mediators; D007334:Insulin-Like Growth Factor I; D016173:Macrophage Colony-Stimulating Factor; D013937:Thymidine Kinase; D015774:Ganciclovir