Modulation of peripheral immune cells by dopaminergic signaling in health and disease: a focus on sex and other influencing factors

Besides the role of dopamine (DA) as an important neurotransmitter in the brain, it also acts as a modulator of diverse immunological functions in the periphery. Peripheral blood mononuclear cells (PBMCs) can produce DA themselves and express dopamine receptors (DRs), thus making them responders to dopaminergic stimulation. Several in vitro and in vivo studies have reported correlations of DA and DR expression with inflammatory conditions, including autoimmune diseases. Moreover, the functional relevance of DR stimulation on immune cells has been described, but with contradictory findings ranging from anti- to pro-inflammatory effects context-dependently. This work aims to deepen the understanding of the role of the dopaminergic system in modulating peripheral immune responses and to identify influencing factors shaping DA-indued effects in health and disease. In this work, PBMCs from female and male healthy controls (HC) and rheumatoid arthritis (RA) patients were analyzed for their basal intracellular DA level using ELISA, and for DR and tyrosine hydroxylase (TH) expression using flow cytometry. Correlations were investigated between DR expression and sex hormones, the maturation stage of B cells, and disease parameters. PBMCs were stimulated in vitro with agonists for D1- or D2-like receptors under physiological or acute/chronic inflammatory conditions. Activation marker expression on B cells, monocytes, and T cells via flow cytometry, cytokine secretion via ELISA, and proliferation of B cells via CFSE assay were measured. To understand the interplay of different cells, B cells or monocytes were depleted from PBMCs and stimulated accordingly. Sex could be identified as a key modulator of the dopaminergic system and the DR-induced functional outcomes. Healthy men exhibited higher DRD1 expression on B cells compared to women. Upregulation of DRD1 expression on male B cells was observed following in vitro stimulation with sex hormones. DR stimulation of PBMCs under physiological conditions led to anti-inflammatory responses in women, while men showed a trend toward pro-inflammatory effects. These effects were primarily attributed to monocytes but driven by B cells, identifying the interplay between cells as another influencing factor. Female RA patients exhibited increased DRD1 expression on B cells, which positively correlated with disease activity and duration, suggesting a pro-inflammatory role for DA during inflammatory processes in women. Functionally, ongoing inflammatory processes also appeared to be a determining factor, as pro-inflammatory immune responses were observed in women under both acute and chronic inflammation. Men showed pro-inflammatory responses to DR stimulation under acute inflammatory conditions, but this was not confirmed for chronic inflammation. In summary, sex and sex hormones, inflammatory processes, and the interplay between different cell types were identified as key factors influencing the dopaminergic system and its functional outcomes. These findings provide unique insights into the role of DA as a modulator of peripheral immune cells in both health and disease. Furthermore, they underscore the relevance of sex-specific therapeutic approaches, when targeting the DR pathway for treating pathologies such as RA or other DA-related diseases.