Role of Dopamine in the Modulation of Macrophage-Mediated Inflammation: Implications for the Neuropathogenesis of NeuroHIV and Drug Abuse

Drug abuse is an important comorbidity in HIV infection and has been linked to changes in the development of HIV-associated neurocognitive disorders (HAND). All drugs of abuse increase extracellular dopamine in the CNS, and data showing correlations between dopaminergic dysfunction and HIV infection of the CNS suggest that inflammation induced by elevated dopamine could enhance the development of HIV-associated neuropathology. However, the precise mechanism(s) by which elevated dopamine could exacerbate the progress of HAND remain unclear. As the primary targets for and responders to HIV in the CNS are myeloid lineage cells, the effects of dopamine on these cells may be a key connection between dopaminergic changes and HIV-associated neuroinflammation. Our data show that dopamine treatment of human macrophages promotes an inflammatory phenotype in these cells by inducing production of the inflammatory mediators IL-1β, IL-6, IL-18, CCL2, CXCL8, CXCL9, and CXCL10. Further, dopamine-mediated modulation of specific cytokines is correlated with macrophage expression of dopamine-receptor transcripts, particularly DRD5, which is expressed at significantly higher levels than other dopamine-receptor subtypes. Mechanistically, these effects are induced, at least in part by dopamine mediated activation of inflammatory pathways, as our data show dopamine activation of the NF-kB pathway is necessary for the increased production of IL-6 and CXCL10. Activation of NF-kB also increases expression of NF-kB modulated genes including NLRP3 and IL-1β that prime the NLRP3 inflammasome complex. Thus, elevated CNS dopamine in the context of HIV and/or drug abuse may potentiate neuroinflammation via the NF-kB pathway. 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.Ph.D., Neuroscience -- Drexel University, 201