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Dissertation
The Impact of Dopamine Receptor Signaling on Myeloid Cell Function: Implications for the Pathogenesis of NeuroHIV
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2021
DOI:
https://doi.org/10.17918/00000925
Abstract
Up to 50% of people living with human immunodeficiency virus, or HIV (PLWH) suffer from some form of neuroHIV, the collection of distinct neuropathologies and neurocognitive impairments associated with HIV infection of the central nervous system (CNS). Current data suggests comorbid substance use, which is disproportionately high in people living with HIV (PLWH), can enhance HIV neuropathogenesis. All substances of abuse increase extracellular dopamine levels in the CNS, and dopamine rich regions of the CNS are particularly sensitive to HIV-associated inflammation and neuronal dysfunction. This suggests that elevations in CNS dopamine are one way in which drugs of abuse can impact neuroHIV. Dopamine is an important neuroimmune modulator and impacts the function of a number of immune cells, including cells of the myeloid lineage. Myeloid cells, primarily macrophages and microglia, are the major producers of virus within the CNS and critical drivers of neuroinflammation. We have shown dopamine increases HIV replication and inflammation in human macrophages, but the mechanism by which it does so is not clear. Here, we expand on these findings and demonstrate that in macrophages, dopamine increases HIV entry through a calcium dependent mechanism mediated, in part, by coupling of the D1-like receptors to Gq. Further, we show that dopamine does not act through NFkB to drive pro-inflammatory cytokine release in microglia, demonstrating differences in dopamine-mediated inflammation between macrophages and microglia. Mechanistically, these differences may be driven by distinct dopamine-receptor pathways. In macrophages, dopamine acts primarily through Gq-PLC-beta to drive calcium release, PKC activation, and AKT phosphorylation, while in microglia, dopamine acts through Gs-cAMP and has an inhibitory effect on AKT. These studies provide evidence that differences in dopamine signaling can impact dopamine's effects on HIV neuropathogenesis, and suggest new pathways that could be therapeutically targeted in the treatment of HIV neurocognitive disorders.
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Details
- Title
- The Impact of Dopamine Receptor Signaling on Myeloid Cell Function
- Creators
- Emily Anne Nickoloff-Bybel
- Contributors
- Peter J. Gaskill (Advisor)Jacqueline M. Barker (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- X, 229 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991015757498404721