| Ironically, although cells require iron for normal functions, iron catalyzes the formation of oxygen radicals that can be detrimental. Thus, intracellular iron must be closely regulated by tightly control of iron uptake and storage. Microglia are one of two cell types that stain robustly for iron in the brain. Iron first appears in microglia during the embryonic period, but then gradually declines. In the normal adult brain, iron is primarily localized to oligodendrocytes. Because accumulation of iron without the ability to sequester it could be toxic, I hypothesized that ferritin cellular expression during development is similar to that seen for iron. My research demonstrated that iron accumulation and ferritin expression overlapped. I also noted that there was a shift in ferritin expression from microglia to oligodendrocytes that was identical to that described for iron and coincided temporally and spatially with the formation of myelin. To further pursue the relationship between ferritin, microglia, and oligodendrocytes, I used a rat model of neonatal hypoxia/ischemia (H/I) to test the hypothesis that H/I would prolong the expression of ferritin in microglia and delay expression in oligodendrocytes. The results support my hypothesis and strongly suggested iron acquisition and ferritin expression by microglia was an integral part of brain development and repair. However, it was not clear what role iron played in microglial function. Thus, I developed a cell culture model of rat microglia to determine the role of iron in microglia. In the course of these studies I discovered a spontaneously occurring immortalized rat microglia cell line (HAPI). The effect of iron on lipopolysaccharide-elicited microglial inflammatory responses was examined using HAPI cells. The results demonstrated that cellular iron status influences the production of nitric oxide and tumor necrosis factor. Finally, I tested the hypothesis that iron status influenced the gene expression profile in response to inflammation. The transcripts expressed in activated microglia during the inflammatory response and those influenced by iron were identified by DNA microarray. The results showed that iron modified microglia inflammatory responses. In summary, my thesis demonstrates that microglia play a key role in the management of brain iron and that microglia-mediated inflammatory processes in the brain can be modulated by iron. |
