NDLI: Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV

Content Provider	Springer Nature : BioMed Central
Author	Matt, Stephanie M. Nolan, Rachel Manikandan, Samyuktha Agarwal, Yash Channer, Breana Oteju, Oluwatofunmi Daniali, Marzieh Canagarajah, Joanna A. LuPone, Teresa Mompho, Krisna Runner, Kaitlyn Nickoloff-Bybel, Emily Li, Benjamin Niu, Meng Schlachetzki, Johannes C. M. Fox, Howard S. Gaskill, Peter J.
Abstract	The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens. Graphical Abstract
Related Links	https://jneuroinflammation.biomedcentral.com/counter/pdf/10.1186/s12974-025-03403-9.pdf
Ending Page	29
Page Count	29
Starting Page	1
File Format	HTM / HTML
ISSN	17422094
DOI	10.1186/s12974-025-03403-9
Journal	Journal of Neuroinflammation
Issue Number	1
Volume Number	22
Language	English
Publisher	BioMed Central
Publisher Date	2025-03-23
Access Restriction	Open
Subject Keyword	Neurosciences Neurology Neurobiology Immunology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology Cellular and Molecular Neuroscience Neurology
Journal Impact Factor	9.3/2023
5-Year Journal Impact Factor	9.8/2023

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