835.12 - Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV

Stephanie Matt (Drexel University College of Medicine), Rachel Nolan (Drexel University College of Medicine, Drexel University College of Medicine), Samyuktha Manikandan (Drexel University College of Medicine), Yash Agarwal (Drexel University College of Medicine), Breana Channer (Drexel University College of Medicine, Drexel University College of Medicine), Joanna Canagarajah (Drexel University College of Medicine), Kaitlyn Runner (Drexel University College of Medicine), Emily Nickoloff-Bybel (Drexel University College of Medicine), Peter Gaskill (Drexel University College of Medicine)

The neurological complications of HIV infection, known as neuroHIV, remain prevalent even in individuals on antiretroviral therapy (ART). Although the mechanism(s) underlying neuroHIV remain undefined, current data suggest that neuroinflammation is central to the development of HIV neuropathogenesis. Neuroinflammation can be exacerbated by substance use disorders, which are highly comorbid with HIV infection and substantively worsen clinical outcomes. Despite distinct mechanisms of action, all substances of abuse increase central nervous system (CNS) dopamine, suggesting that dopamine is a common mechanism by which addictive drugs potentiate neuroHIV. Our published data show that dopamine increases the production of inflammatory cytokines such as IL-1β in human microglia and macrophages, but the mechanisms by which dopamine drives inflammation are not clear. Studies indicate that D1-like dopamine receptors (DRD1, DRD5) mediate inflammatory activity while D2-like dopamine receptors (DRD2, DRD3, and DRD4) mediate anti-inflammatory activity, and we have shown that human macrophages and microglia have higher expression of D1-like receptors. Therefore, we hypothesize that dopamine-mediated production of IL-1β in CNS myeloid cells is regulated by the ratio of different dopamine receptor expression levels and can be exacerbated by HIV infection. Our data in primary macrophages indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, but that changes in DRD2 expression can alter the magnitude of the dopamine-mediated increase in IL-1β. We confirm this in human microglia cell lines, showing that dopamine only increases IL-1β gene and protein expression in microglia with a high ratio of D1-like receptors to D2-like receptors. Further, antagonizing dopamine receptor expression with the pan-dopamine receptor antagonist flupentixol or decreasing the D1-like/D2-like ratio by overexpressing DRD2 diminishes the dopamine-mediated increase of IL-1β. We also show that the effects of dopamine on IL-1β are potentiated in the presence of HIV infection in both microglial cell lines and iPSC-derived microglia. Ongoing studies are examining the role of epigenetic regulation in the effects of dopamine and HIV on inflammation in these myeloid systems. Due to the prevalence of both substance use disorders and the increasing use of dopamine-modulating therapeutics, a detailed understanding of dopamine-mediated changes in inflammation will be critical to effectively tailor ART regimens to HIV-infected individuals using these drugs.

This work is supported by the National Institutes of Drug Abuse, DA039005 and DA049227 (PJG), and the W.W. Smith Charitable Trust Foundation Grant A2003 (PJG). lt;br class="t-last-br"gt;