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

Abstract

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.

Immunomodulatory Effects of Dopamine in Inflammatory Diseases

“…D2-like DRs participate in a cAMP-independent pathway to regulate macrophage phagocytic function, thus reducing the secretion of IL-2, IL-4, and IFN-g (104), the effect of which is concentration-dependent. Studies demonstrated that D2-like DRs decrease the production of TNF-a, IL-6, and CCL2 at 10 −8 M concentration(105), while increase the production of IL-6 significantly at 2 and 20 × 10 −6 M (106) concentration.…”

Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

“…Treatment with IL-10 (50 ng/mL) was used as a positive control, as this cytokine increases CCR5 expression in human monocytes, macrophages, and microglia (79,102,103). This use of a positive control in hMDM is similar to what we and others have published (50,60,104), as there is considerable variation in the hMDM inflammatory response to environmental stimuli (105-107). Therefore, donors in which IL-10 did not increase CCR5 at 1 hour were excluded from the analysis.…”

“…These data suggest that individual variations in the response to dopamine could alter the effectiveness of MVC, changing the efficacy of antiretroviral therapy in HIV-infected substance abusers. As differences in dopamine receptor levels can contribute to donor-specific responses to dopamine (50), the donor responses to MVC and/or dopamine were compared to expression of all five subtypes of dopamine receptors (D1-like, DRD1 and DRD5; and D2-like, DRD2, 3, 4). These correlations were performed using expression of dopamine receptor transcripts by qPCR due to the lack of effective antibodies against human dopamine receptors and the inability of existing antibodies to differentiate between DRD1 and DRD5.…”

“…Different classes of drugs have distinct mechanisms of action, but the use of all addictive substances induces the production of the neurotransmitter dopamine in the mesocorticolimbic system (44,45). Commonly studied as a central component of the reward or motor pathways, increasing evidence indicates that dopamine also regulates immune function (46)(47)(48)(49)(50)(51). Immune cells in the CNS and periphery express all five subtypes of dopamine receptors (DRD1, 2, 3, 4, 5) and other dopamine-related proteins, enabling dopamine to regulate a variety of immune functions in both homeostatic and pathological conditions (52,53).…”

“…Exposure to dopamine concentrations induced by substance abuse increases HIV replication by increasing the number of infected macrophages (54)(55)(56). Further, dopamine has been shown to alter a variety of other functions that differ by cell type but include modulation of cytokine and chemokine secretion, changes in phagocytic activity, proliferation and chemotaxis (50,(57)(58)(59)(60).…”