Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages
Year: 2026
Type: article
Abstract: Despite growing evidence that dopamine acts as an innate immune inflammatory mediator, the molecular mechanisms by which dopamine modulates human immune function are incompletely defined. Here, we define the pathway in which dopamine induces robust IL-6 secretion in primary human monocyte-derived macrophages (hMDMs) through mitochondrial stress. Dopamine initiates a transient mitochondrial membrane depolarization that leads to sustained alterations in mitochondrial dynamics, including morphology and metabolism. These events promote the release of mtDNA into the cytoplasm, triggering the cGAS-STING pathway and NF-κB signaling. Pharmacological inhibition at multiple nodes of this pathway attenuates IL-6 secretion, establishing mitochondrial dysfunction and cGAS-STING signaling as central mediators of dopamine-driven IL-6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. These findings highlight a potential link between dopamine signaling and systemic inflammation and suggest that differences in dopamine receptor expression may contribute to inter-individual variation in innate immune responses.
Source: Cell Reports
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G1146315651, G3658037551, Advancing Cancer Research through Comprehensive Proteomics and Metabolomics Analyses, Comprehensive NeuroHIV Center, Dopaminergic immunomodulation drives macrophage inflammation during HIV infection, Defining molecular mechanisms by which stimulant evoked dopamine drives inflammation and neuronal dysfunction in neuroHIV, Examination of epigenetic spatial architecture in the CNS as a method to understand cocaine relapse in ecoHIV infected mice, Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations, Uncovering HIV/opioid effects in the brain at the single cell level: transcription, chromatin accessibility, and reservoir analysis in the SIV/cART/morphine/rhesus monkey model, Consolidated Basic Cancer Research Program, Dysregulation of glutamate transporter-dependent neurovascular coupling in Alzheimer's disease, The role of antidepressants in central and peripheral myeloid HIV persistence and inflammation, G9001170202, G9001170551, G9001170605, G9001171112
OpenAlex ID: W7221335699