Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages

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.