Characterization and function of the human macrophage dopaminergic system: implications for CNS disease and drug abuse

Abstract

BackgroundPerivascular macrophages and microglia are critical to CNS function. Drugs of abuse increase extracellular dopamine in the CNS, exposing these cells to elevated levels of dopamine. In rodent macrophages and human T-cells, dopamine was shown to modulate cellular functions through activation of dopamine receptors and other dopaminergic proteins. The expression of these proteins and the effects of dopamine on human macrophage functions had not been studied.MethodsTo study dopaminergic gene expression, qRT-PCR was performed on mRNA from primary human monocyte derived macrophages (MDM). Expression and localization of dopaminergic proteins was examined by immunoblotting isolated plasma membrane, total membrane and cytosolic proteins from MDM. To characterize dopamine-mediated changes in cytokine production in basal and inflammatory conditions, macrophages were treated with different concentrations of dopamine in the presence or absence of LPS and cytokine production was assayed by ELISA. Statistical significance was determined using two-tailed Students’ T-tests or Wilcoxen Signed Rank tests.ResultsThese data show that MDM express mRNA for all five subtypes of dopamine receptors, and that dopamine receptors 3 and 4 are expressed on the plasma membrane. MDM also express mRNA for the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC). DAT is expressed on the plasma membrane, VMAT2 on cellular membranes and TH and AADC are in the cytosol. Dopamine also alters macrophage cytokine production in both untreated and LPS-treated cells. Untreated macrophages show dopamine mediated increases IL-6 and CCL2. Macrophages treated with LPS show increased IL-6, CCL2, CXCL8 and IL-10 and decreased TNF-α.ConclusionsMonocyte derived macrophages express dopamine receptors and other dopaminergic proteins through which dopamine may modulate macrophage functions. Thus, increased CNS dopamine levels due to drug abuse may exacerbate the development of neurological diseases including Alzheimer’s disease and HIV associated neurological disorders.

Differential Response of Dopamine Mediated by β-Adrenergic Receptors in Human Keratinocytes and Macrophages: Potential Implication in Wound Healing

“…Besides, dopamine significantly increased the levels of the chemokine IL-8 in THP-1 macrophages, which is similar to the observations made by Gaskill [11] in LPS-stimulated human mononuclear-derived macrophages. The stimulatory effect of dopamine on the secretion of IL-8 was partially reversed by the β-adrenergic blocker propranolol, similar to the effect previously described in keratinocytes, where dopamine stimulated the production of IL-6 and IL-8 mainly mediated by β-ARs [5].…”

“…In addition to MMPs, keratinocytes and macrophages produce different inflammatory molecules such as cytokines [6, 44]. Gaskill et al [11] demonstrated that dopamine (2 × 10 –8 to 2 × 10 –5 M) may either decrease or increase the production of cytokines (IL-6, CCCL-2, IL-8, IL-10, TNF-α) by PBMC-derived macrophages and depending on whether the cells are activated or not by bacterial LPS. However, it is known that the effect of dopamine depends not only on the activation status of the cell population involved, but also on the concentration of the catecholamine as well as on the mechanism involved (type of receptor/oxidative mechanism).…”

“…The activity of such receptors can be regulated in response to several stimuli [10]. In addition, keratinocytes and macrophages can synthesize and degrade catecholamines and express dopaminergic and α/β-ARs on their surface [11]. At the epidermal level, electrophysiological studies have suggested that dopamine accelerates the skin barrier recovery [12].…”

Inhibition of Dengue Virus Replication by a Class of Small-Molecule Compounds That Antagonize Dopamine Receptor D4 and Downstream Mitogen-Activated Protein Kinase Signaling

“…Notably, SKI-417616 inhibits the phosphorylation of ERK in response to dopamine but does not affect the repression of cAMP signaling, a second arm of DRD4 downstream signaling. The expression and activity of dopamine receptors are typically considered to be specific to neurons; however, several recent reports have demonstrated expression of dopamine receptors on rodent and human macrophages (32,33), a primary target cell of DENV infection. Although the exact mechanism has not yet been elucidated, dopamine receptors expressed on macrophages appear to play an important role in regulating cytokine production and modulating immune function (32).…”

“…The expression and activity of dopamine receptors are typically considered to be specific to neurons; however, several recent reports have demonstrated expression of dopamine receptors on rodent and human macrophages (32,33), a primary target cell of DENV infection. Although the exact mechanism has not yet been elucidated, dopamine receptors expressed on macrophages appear to play an important role in regulating cytokine production and modulating immune function (32). Whether this function of macrophage-expressed dopamine receptors is related to the effect of DRD4 inhibition by DHBTs on DENV infection is unclear and warrants further investigation.…”