Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV
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 immunoreg...
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BMC
2025-03-01
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| Series: | Journal of Neuroinflammation |
| Online Access: | https://doi.org/10.1186/s12974-025-03403-9 |
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| author | Stephanie M. Matt Rachel Nolan Samyuktha Manikandan Yash Agarwal Breana Channer Oluwatofunmi Oteju Marzieh Daniali Joanna A. Canagarajah Teresa LuPone Krisna Mompho Kaitlyn Runner Emily Nickoloff-Bybel Benjamin Li Meng Niu Johannes C. M. Schlachetzki Howard S. Fox Peter J. Gaskill |
| author_facet | Stephanie M. Matt Rachel Nolan Samyuktha Manikandan Yash Agarwal Breana Channer Oluwatofunmi Oteju Marzieh Daniali Joanna A. Canagarajah Teresa LuPone Krisna Mompho Kaitlyn Runner Emily Nickoloff-Bybel Benjamin Li Meng Niu Johannes C. M. Schlachetzki Howard S. Fox Peter J. Gaskill |
| author_sort | Stephanie M. Matt |
| collection | DOAJ |
| description | 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 |
| format | Article |
| id | doaj-art-cc6e6ffad2ac49539c6460b971ce42ab |
| institution | OA Journals |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Journal of Neuroinflammation |
| spelling | doaj-art-cc6e6ffad2ac49539c6460b971ce42ab2025-08-20T02:19:58ZengBMCJournal of Neuroinflammation1742-20942025-03-0122112910.1186/s12974-025-03403-9Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIVStephanie M. Matt0Rachel Nolan1Samyuktha Manikandan2Yash Agarwal3Breana Channer4Oluwatofunmi Oteju5Marzieh Daniali6Joanna A. Canagarajah7Teresa LuPone8Krisna Mompho9Kaitlyn Runner10Emily Nickoloff-Bybel11Benjamin Li12Meng Niu13Johannes C. M. Schlachetzki14Howard S. Fox15Peter J. Gaskill16Department of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Medicine, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineGraduate School of Biomedical Sciences and Professional Studies, Drexel University College of MedicineDepartment of Microbiology and Immunology, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Pharmacology and Physiology, Drexel University College of MedicineDepartment of Cellular and Molecular Medicine, University of California San DiegoDepartment of Neurological Sciences, University of Nebraska Medical CenterDepartment of Cellular and Molecular Medicine, University of California San DiegoDepartment of Neurological Sciences, University of Nebraska Medical CenterDepartment of Pharmacology and Physiology, Drexel University College of MedicineAbstract 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 Abstracthttps://doi.org/10.1186/s12974-025-03403-9 |
| spellingShingle | Stephanie M. Matt Rachel Nolan Samyuktha Manikandan Yash Agarwal Breana Channer Oluwatofunmi Oteju Marzieh Daniali Joanna A. Canagarajah Teresa LuPone Krisna Mompho Kaitlyn Runner Emily Nickoloff-Bybel Benjamin Li Meng Niu Johannes C. M. Schlachetzki Howard S. Fox Peter J. Gaskill Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV Journal of Neuroinflammation |
| title | Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV |
| title_full | Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV |
| title_fullStr | Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV |
| title_full_unstemmed | Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV |
| title_short | Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV |
| title_sort | dopamine driven increase in il 1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by hiv |
| url | https://doi.org/10.1186/s12974-025-03403-9 |
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