Role of Macrophage Dopamine Receptors in Mediating Cytokine Production: Implications for Neuroinflammation in the Context of HIV-Associated Neurocognitive Disorders

• DOI: 10.1007/s11481-018-9825-2
• Publication Date: 2018-12-05T04:02:57Z
• Authors: R. A. Nolan; R. Muir; K. Runner; E. K. Haddad; P. J. Gaskill
• Keywords: 0301 basic medicine; 03 medical and health sciences; AIDS Dementia Complex; Dopamine; Macrophages; Cytokines; Humans; Receptors, Dopamine D5; Cells, Cultured; 3. Good health

Despite the success of combination anti-retroviral therapy (cART), around 50% of HIV-infected individuals still display a variety of neuropathological and neurocognitive sequelae known as NeuroHIV. Current research suggests these effects are mediated by long-term changes in CNS function in response to chronic infection and inflammation, and not solely due to active viral replication. In the post-cART era, drug abuse is a major risk-factor for the development of NeuroHIV, and increases extracellular dopamine in the CNS. Our lab has previously shown that dopamine can increase HIV infection of primary human macrophages and increase the production of inflammatory cytokines, suggesting that elevated dopamine could enhance the development of HIV-associated neuropathology. However, the precise mechanism(s) by which elevated dopamine could exacerbate NeuroHIV, particularly in chronically-infected, virally suppressed individuals remain unclear. To determine the connection between dopaminergic alterations and HIV-associated neuroinflammation, we have examined the impact of dopamine exposure on macrophages from healthy and virally suppressed, chronically infected HIV patients. Our data show that dopamine treatment of human macrophages isolated from healthy and cART-treated donors promotes production of inflammatory mediators including IL-1β, IL-6, IL-18, CCL2, CXCL8, CXCL9, and CXCL10. Furthermore, in healthy individuals, dopamine-mediated modulation of specific cytokines is correlated with macrophage expression of dopamine-receptor transcripts, particularly DRD5, the most highly-expressed dopamine-receptor subtype. Overall, these data will provide more understanding of the role of dopamine in the development of NeuroHIV, and may suggest new molecules or pathways that can be useful as therapeutic targets during HIV infection.