Selective Ablation of Proliferating Microglial Cells Exacerbates Ischemic Injury in the Brain

By Mélanie Lalancette–Hébert, G. Gowing, Alain R Simard, Y. Weng, J. Kriz. Journal of Neuroscience, 2007

901 citations recorded by the source corpus.

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 ∼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.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/615755c4faef5a87f90a90d0a132322aed7a2938

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Citations in the corpus

Role of Microglia in Neurotrauma (2010, neutral): “For example, recent studies have suggested differences in protein expression profiles between macrophages and microglia, including differences in the level of CD45 expression(15,16) and galectin-3/MAC-2 expression.(17) Furthermore, macrophages have twice as much proteolytic activity as microglia, an”
Early-Life Programming of Later-Life Brain and Behavior: A Critical Role for the Immune System (2009, background): “For instance, they produce neurotrophic factors that aid in cellular repair, and recruit immune cells into the brain, which aid in clearing infection or cellular debris (Lalancette-Hebert et al., 2007).”
Microglia/Macrophage Polarization Dynamics Reveal Novel Mechanism of Injury Expansion After Focal Cerebral Ischemia (2012, background): “Microglia/macrophage activation is proposed to benefit the injured brain by removing cell debris and restoring tissue integrity.(12,15) However, mounting evidence reveals that drastic microglia/macrophage activation leads to secondary expansion of ischemic infarction and deterioration of neurologica”
Microglia: active sensor and versatile effector cells in the normal and pathologic brain (2007, background): “When these animals are challenged by transient middle cerebral artery occlusion, leading to an ischemic injury, the ablation of microglial cells results in a significant increase in the size of the infarct, associated with an increase in apoptotic neurons [ 81 ].”
Inflammatory mechanisms in ischemic stroke: role of inflammatory cells (2010, background): “bral ischemia and may last for several weeks after initial injury [38, 39].”
Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro (2013, background): “The importance of microglia in protecting the brain is illustrated by the observation that complete blockade of microglial activity exacerbates brain damage in adult and neonatal hypoxic ischemic injury models (Lalancette-Hebert et al., 2007; Faustino et al., 2011).”
Inflammation and Stroke: An Overview (2016, background): “Eliminating proliferating microglia/macrophages by ganciclovir treatment in mice that express herpes simplex virus-1 thymidine kinase in the myeloid lineage increased ischemic brain injury and reduced expression of the neurotrophic cytokine insulin-like growth factor 1 [43].”
The immunology of stroke: from mechanisms to translation (2011, background): “For example, microglia are required for the full expression of insulin-like growth factor 1 (IGF-1”
Immune responses to stroke: mechanisms, modulation, and therapeutic potential. (2020, background): “While microglia are proinflammatory and exhibit cytotoxic activity in vitro, microglial depletion worsens stroke outcome (49, 50).”