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The Role of Hypoxia-Inducible Factor-1 (HIF-1) in Microglia in Ischemic Stroke

The Role of Hypoxia-Inducible Factor-1 (HIF-1) in Microglia in Ischemic Stroke
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Stroke is the third leading cause of death and it is the most frequent cause of serious and long term disability. Microglia are brain resident macrophages responding to various stimuli to exert appropriate inflammatory responses. Recently, a number of studies have demonstrated that microglial activation thereby neuroinflammation is commonly observed in several brain disorders including stroke. Cells respond to hypoxic conditions by activating hypoxia-inducible factor (HIF), a transcription factor further activating many genes involved in inflammatory responses, cell migration, and angiogenesis. It has been reported that HIF in neurons is critically required to protect neurons against ischemic stroke. However, the role of HIF in microglia is still poorly understood. In this thesis, I utilized a novel strain of myeloid-specific Hif-1α knockout (KO) mice and found that these mice behaviorally recovered faster than wild-type (WT) mice when challenged from ischemic stroke by middle cerebral artery occlusion (MCAO). By performing immunostaining, I observed that there were fewer microglia and higher numbers of neurons were preserved in the hippocampal areas of Hif-1α KO mice at 5 days following MCAO. Furthermore, isolated microglia from these animals exhibited impaired phagocytosis, chemotaxis, reactive oxygen species (ROS) production, and cytokine production. Knocking down CD36 or Mfge8, HIF-1 downstream target genes known to regulate phagocytosis in BV2 microglia cell line phenocopied in vivo microglia isolated from Hif-1α KO mice at 5 days following MCAO, indicating that CD36 and MFG-E8 may be therapeutic targets in microglia in ischemic stroke patients. In conclusion, I demonstrated that HIF-1 in microglia is a critical regulator for inflammatory phagocytosis in neuroinflammation in ischemic stroke utilizing our novel myeloid-specific Hif-1α KO mice.
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