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

@article{lalancettehebert07selective, abstract = {Me´lanie Lalancette-He´bert, Genevie`ve Gowing, Alain Simard, Yuan Cheng Weng, and Jasna KrizDepartment of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l'Universite´ Laval, Quebec, Canada G1V 4G2Here we report in vivo evidence of a neuroprotective role of proliferating microglial cells in cerebral ischemia. Using transgenic miceexpressing a mutant thymidine kinase form of herpes simplex virus driven by myeloid-specific CD11b promoter and ganciclovir treatmentas a tool, we selectively ablated proliferating (Mac-2 positive) microglia after transient middle cerebral artery occlusion. The seriesof experiments using green fluorescent protein-chimeric mice demonstrated that within the first 72 h after ischemic injury, the Mac-2marker [unlike Iba1 (ionized calcium-binding adapter molecule 1)] was preferentially expressed by the resident microglia. Selectiveablation of proliferating resident microglia was associated with a marked alteration in the temporal dynamics of proinflammatorycytokine 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 a100\% colocalizationbetween IGF-1 positive cells and Mac-2, a marker of activated/proliferating resident microglia. Conversely, stimulation ofmicroglial proliferation after cerebral ischemia by M-CSF (macrophage colony stimulating factor) resulted in a 1.9-fold increase in IGF-1levels and a significant increase of Mac2cells. Our findings suggest that a postischemic proliferation of the resident microglial cells mayserve as an important modulator of a brain inflammatory response. More importantly, our results revealed a marked neuroprotectivepotential of proliferating microglia serving as an endogenous pool of neurotrophic molecules such as IGF-1, which may open newtherapeutic avenues in the treatment of stroke and other neurological disorders.Key words: glia; growth factor; ischemia; mice; neuroinflammation; neuroprotection; transgenic}, author = {Hebert, Lalancette M. and Gowing, G. and Simard, A. and Weng, Y. C. and Kriz, J.}, citeulike-article-id = {4300450}, journal = {Journal of Neuroscience}, keywords = {file-import-09-04-11}, number = {10}, pages = {2596}, posted-at = {2009-04-11 13:31:30}, priority = {2}, publisher = {Soc Neuroscience}, title = {{Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain}}, volume = {27}, year = {2007} }

TY - JOUR ID - lalancettehebert07selective L3 - citeulike-article-id:4300450 N2 - Me´lanie Lalancette-He´bert, Genevie`ve Gowing, Alain Simard, Yuan Cheng Weng, and Jasna KrizDepartment of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l’Universite´ Laval, Quebec, Canada G1V 4G2Here we report in vivo evidence of a neuroprotective role of proliferating microglial cells in cerebral ischemia. Using transgenic miceexpressing a mutant thymidine kinase form of herpes simplex virus driven by myeloid-specific CD11b promoter and ganciclovir treatmentas a tool, we selectively ablated proliferating (Mac-2 positive) microglia after transient middle cerebral artery occlusion. The seriesof experiments using green fluorescent protein-chimeric mice demonstrated that within the first 72 h after ischemic injury, the Mac-2marker [unlike Iba1 (ionized calcium-binding adapter molecule 1)] was preferentially expressed by the resident microglia. Selectiveablation of proliferating resident microglia was associated with a marked alteration in the temporal dynamics of proinflammatorycytokine 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 a100% colocalizationbetween IGF-1 positive cells and Mac-2, a marker of activated/proliferating resident microglia. Conversely, stimulation ofmicroglial proliferation after cerebral ischemia by M-CSF (macrophage colony stimulating factor) resulted in a 1.9-fold increase in IGF-1levels and a significant increase of Mac2cells. Our findings suggest that a postischemic proliferation of the resident microglial cells mayserve as an important modulator of a brain inflammatory response. More importantly, our results revealed a marked neuroprotectivepotential of proliferating microglia serving as an endogenous pool of neurotrophic molecules such as IGF-1, which may open newtherapeutic avenues in the treatment of stroke and other neurological disorders.Key words: glia; growth factor; ischemia; mice; neuroinflammation; neuroprotection; transgenic IS - 10 JF - Journal of Neuroscience EP - 2596 TI - {Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain} PB - Soc Neuroscience VL - 27 KW - file-import-09-04-11 AU - Hebert, Lalancette AU - Gowing, G AU - Simard, A AU - Weng, YC AU - Kriz, J PY - 2007/// ER -