Date of Completion
Microglia, Intracerebral Hemorrhage, TGF-b1, neuroinflammation
Lauren H. Sansing
Field of Study
Doctor of Philosophy
Intracerebral hemorrhage (ICH) is a devastating subset of stroke that has a high mortality rate and no specific treatment. ICH results from the rupture of blood vessels within the brain, leading to microglial activation. Upon activation, microglia can polarize into many phenotypes ranging from pro-inflammatory to a phenotype associated with wound healing and repair. Using bone marrow chimeras, we studied the role of CX3CR1 independently on monocytes and microglia. We found that CX3CR1 on Ly6Clo monocytes is dispensable after ICH. Interestingly, Ly6Clo monocytes enter the brain parenchyma independently of CX3CR1 expression. We utilized the CX3CR1-regulation of microglial activation to study microglial responses after ICH. We found that microglial dysregulation leads to poor functional outcomes and a reduction in TGF-β1 gene expression. Through unbiased transcriptional analysis, we found that microglia transition from a pro-inflammatory phenotype to a phenotype that promotes wound healing and repair; this transition is likely mediated by TGF-β1. In vitro, TGF-β1 decreased microglial pro-inflammatory gene expression and TNF production. In vivo, TGF-β1 improved functional outcomes at 24 hours after ICH and decreased microglial IL-6 gene expression. Furthermore, patients who increased plasma TGF-β1 concentrations from 6 to 72 hours after ICH had better outcomes at 90 days. We investigated whether microglia aid in repair by phagocytosing myelin debris after ICH. In vivo, myeloid cells phagocytose myelin 7 days after ICH. In vitro, microglia phagocytose myelin, which resulted in a decrease in pro-inflammatory gene expression. Taken together, our data suggest that TGF-β1 modulates microglial-mediated neuroinflammation and promotes functional recovery after ICH. Our data also suggests that microglia aid in recovery after ICH through the phagocytosis of myelin debris and that phagocytosis quells microglial pro-inflammatory responses.
Taylor, Roslyn, "Microglial Responses in Recovery after Intracerebral Hemorrhage" (2016). Doctoral Dissertations. 1228.