Journal article
Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV
Journal of neuroinflammation, v 22(1), 91
23 Mar 2025
PMID: 40122818
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV
- Creators
- Stephanie M Matt - Drexel UniversityRachel Nolan - Drexel UniversitySamyuktha Manikandan - Drexel UniversityYash Agarwal - Drexel UniversityBreana Channer - Drexel UniversityOluwatofunmi Oteju - Drexel UniversityMarzieh Daniali - Drexel UniversityJoanna A Canagarajah - Drexel UniversityTeresa LuPone - Drexel UniversityKrisna Mompho - Drexel UniversityKaitlyn Runner - Drexel UniversityEmily Nickoloff-Bybel - Drexel UniversityBenjamin Li - University of California, San DiegoMeng Niu - University of Nebraska Medical CenterJohannes C M Schlachetzki - University of California, San DiegoHoward S Fox - University of Nebraska Medical CenterPeter J Gaskill - Drexel University
- Publication Details
- Journal of neuroinflammation, v 22(1), 91
- Publisher
- BMC
- Number of pages
- 29
- Grant note
- K01 MH132466 / NIMH NIH HHS DA039005 / NIDA NIH HHS DA049227 / NIDA NIH HHS DA057337 / NIDA NIH HHS R21 DA049227 / NIDA NIH HHS DA058051 / NIDA NIH HHS A2003 / WW Smith MH132466 / NIMH NIH HHS T32 MH079785 / NIMH NIH HHS T32-MH079785 / T32-MH079785
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Pharmacology and Physiology
- Web of Science ID
- WOS:001450007400001
- Scopus ID
- 2-s2.0-105000779348
- Other Identifier
- 991022041951404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Neurosciences