Epigenetic regulation of inflammation by dopamine in primary human macrophages.

Introduction: 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 demonstrates 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. Methods: Primary human monocyte-derived macrophages were treated with dopamine, and DNA methylation at the IL-1β proximal promoter was evaluated alongside IL-1β and epigenetic enzyme gene expression. Associations between donor characteristics, dopamine receptor expression, and dopamine-induced epigenetic responses were also examined. Results: Dopamine increased DNA methylation at the IL-1β proximal promoter in a DNMT-dependent manner while concurrently increasing IL-1β gene expression. Dopamine treatment also upregulated the expression of several key epigenetic regulators, including TET2, HDAC2, and HDAC6, suggesting coordinated regulation of both DNA methylation and histone modifications that shape inflammatory transcription. Furthermore, 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. Discussion: 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.