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Montilla, J.

Publications and source records attributed to Montilla, J..

2 recordsLinked to original sources
bioRxiv2026

It's Not Rewarding for Mitochondria: Dopamine-Induced Mitochondrial Dysfunction Activates cGAS-STING to Drive IL-6 Secretion in Macrophages

Despite increasing data demonstrating dopamine as an inflammatory mediator of the innate immune system, the molecular mechanisms underlying its effects in human cells remain incompletely defined. Here, we define an unrecognized 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, in a time-dependent manner. These events promote the mtDNA release into the cytoplasm, triggering cGAS-STING pathway and downstream NF-{kappa}B 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 IL6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. Together, these findings redefine the interface between dopamine signaling and systemic inflammation and highlight an unrecognized source of inter-individual variation in immune responses. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/719926v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@e2c133org.highwire.dtl.DTLVardef@fa0a15org.highwire.dtl.DTLVardef@1ac1f91org.highwire.dtl.DTLVardef@14c8c53_HPS_FORMAT_FIGEXP M_FIG C_FIG Dopamine induces mitochondrial dysfunction mediated through dopamine receptors signaling. This includes alterations in mitochondrial membrane potential, leading to excessive DRP1-mediated mitochondrial fission, increased production of mitochondrial superoxide, and metabolic reprogramming toward enhanced glycolysis with reduced oxidative phosphorylation. Sustained mitochondrial damage is further exacerbated by impaired mitophagy, resulting in the release of mitochondrial DNA (mtDNA) into the cytoplasm. Cytosolic mtDNA, acting as a double-stranded DNA ligand, activates the cGAS-STING pathway, which subsequently induces NF-{kappa}B signaling, ultimately driving the production and secretion of the pro-inflammatory cytokine IL-6. Created on Biorender.com.

immunology↗
bioRxiv2026

Epigenetic Regulation of Inflammation by Dopamine in Primary Human Macrophages

While dopamine is a monoamine neurotransmitter best known for its roles in reward, motivation, and motor function in the central nervous system, its actions extend beyond neurons and can influence non-neuronal cells via epigenetic mechanisms. An increasing body of literature corroborates that dopamine signaling is important in immune cells, which express dopamine receptors (DRD1-DRD5) as well as the molecular machinery for dopamine synthesis and metabolism. Dopamine can regulate inflammatory activity, cell trafficking, and disease pathology, yet the epigenetic mechanisms underlying these effects remain poorly understood. Here, we show that in primary human monocyte-derived macrophages, dopamine increases DNA methylation at the IL-1{beta} proximal promoter in a DNMT-dependent manner, while concurrently upregulating IL-1{beta} gene expression. Dopamine also increases the expression of key epigenetic regulators, including TET2, HDAC2, and HDAC6, suggesting coordinated changes in both DNA methylation and histone modifications that shape inflammatory transcription. Importantly, baseline dopamine receptor expression and donor demographics, including sex and age, influence the magnitude of these epigenetic responses, highlighting inter-individual variability in macrophage sensitivity to dopaminergic signaling. These findings establish dopamine as a modulator of macrophage inflammation via epigenetic remodeling and provide a mechanistic framework for understanding how peripheral immune cells respond to dopaminergic cues. By linking dopamine signaling, epigenetic regulation, and innate immunity, this work identifies potential targets for therapeutic intervention and supports the use of accessible human immune cells to investigate dopaminergic dysregulation in neuroimmunological disorders.

immunology↗