Dopamine mediates mature monocyte migration in the context of HIV neuropathogenesis and substance abuse
Coley, Jacqueline Seki
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Despite the effectiveness of antiretroviral therapies, CNS complications due to HIV infection persist in a significant number of HIV positive people. HIV enters the brain within two weeks of peripheral infection by the transmigration of infected monocytes across the blood brain barrier. Once in the brain, virions are produced, which can infect other monocytes, perivascular macrophages, microglia, and astrocytes. Inflammation resulting from viral proteins and host factors continues even in the presence of antiretroviral therapy, and this chronic low level inflammation damages neurons and leads to HIV associated neurocognitive disorders. Monocytes are a major cell type involved in this inflammation, as they are the cells that initiate this neuroinflammation and perpetuate it by their continued influx into the CNS. Drug abuse and HIV infection have long been associated, and many HIV infected drug abusers exhibit worse neurocognitive impairments. A common mechanism by which drugs assert their addictive effects is by increasing extracellular dopamine in the brain. Dopamine, a major neurotransmitter involved in reward and cognition, has been shown to exacerbate and accelerate CNS disease in SIV infected macaques, and this was characterized by increased influx of monocytes into the brain. Our laboratory found that dopamine increases transmigration of monocytes across an in vitro BBB model alone and in combination with CXCL12. We hypothesized that increased dopamine in the brains of HIV infected drug abusers increases the migration of mature CD14+CD16+ monocytes once they are within the CNS. This increased migration is mediated, in part, by the activation of dopamine receptors on CD14+CD16+ monocytes, altering their motility and adhesion. This project focused on characterizing the effects of dopamine on monocyte migration. We demonstrated that monocytes express functional dopamine receptors. We also showed that dopamine increased the migration of monocytes but that the movement is not gradient dependent. Dopamine increased the adhesion of monocytes, as compared to media only. These findings suggest that in HIV infected individuals who take illicit drugs, increased CNS dopamine may increase the accumulation of monocytes around synapses of dopaminergic neurons, damaging these neurons and increasing the severity of neurocognitive impairment in HIV infected drug abusers.
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