PERIPHERIN EXPRESSION IN ASTROCYTES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have previously reported that a number of astrocytes can express VCAM-1 and peripherin, an intermediate filament normally found in peripheral neurons. We have also shown that MCP-3 is upregulated close to the blood-brain barrier at the same time. Our hypothesis was that these astrocytes had been activated by viral-infected cells and were a catalyst for the development of encephalitis. Using ex vivo and in vitro models, we examined the timing of increased expression of peripherin in astrocytes, and the concomitant secretion of chemokines. Astrocytes had decreased GFAP expression coincident with increased peripherin. At this time, they were also actively secreting the chemokine MCP-3. This chemokine is important for monocyte migration into brain and the concomitant disruption of the BBB. Thus, MCP-3 is important in neuropathogenesis. It was noted that astrocytes also had increased expression of S100b protein following incubation with SIV infected macrophages. "Cold chase" studies revealed that astrocytes have the capacity to revert to their native state of low peripherin with high GFAP intermediate filaments and low expression of inflammatory cytokines / chemokines. Thus, the inflammatory stimulus is necessary and sufficient for the production of a mediator that can lead to BBB disruption. Astrocytes have a plasticity of expression of this intermediate filament. This coincides with the synthesis and secretion of biologically relevant chemokines for the development of encephalitis and disruption of the blood-brain barrier.