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

Peter J. Gaskill, Loreto Carvallo, Eliseo A. Eugenin, Joan W. Berman

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Background: Perivascular 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.Methods: To 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.Results: These 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.Conclusions: Monocyte 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.

Original languageEnglish (US)
Article number203
JournalJournal of Neuroinflammation
Volume9
DOIs
StatePublished - Aug 18 2012

Fingerprint

Central Nervous System Diseases
Substance-Related Disorders
Macrophages
Dopamine
Dopamine Receptors
Vesicular Monoamine Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Cell Membrane
Tyrosine 3-Monooxygenase
Cytokines
Messenger RNA
Interleukin-6
Proteins
Aromatic-L-Amino-Acid Decarboxylases
Carboxy-Lyases
Microglia
Street Drugs
Nonparametric Statistics
Nervous System Diseases
Immunoblotting

Keywords

  • Aromatic amino acid decarboxylase
  • Cytokine
  • Dopamine
  • Dopamine transporter
  • Drug abuse
  • Monocyte derived macrophage
  • Neuroinflammation dopamine receptor
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

Characterization and function of the human macrophage dopaminergic system : Implications for CNS disease and drug abuse. / Gaskill, Peter J.; Carvallo, Loreto; Eugenin, Eliseo A.; Berman, Joan W.

In: Journal of Neuroinflammation, Vol. 9, 203, 18.08.2012.

Research output: Contribution to journalArticle

@article{91064849067d42ffa8930ae5aeda723a,
title = "Characterization and function of the human macrophage dopaminergic system: Implications for CNS disease and drug abuse",
abstract = "Background: Perivascular 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.Methods: To 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.Results: These 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.Conclusions: Monocyte 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.",
keywords = "Aromatic amino acid decarboxylase, Cytokine, Dopamine, Dopamine transporter, Drug abuse, Monocyte derived macrophage, Neuroinflammation dopamine receptor, Tyrosine hydroxylase",
author = "Gaskill, {Peter J.} and Loreto Carvallo and Eugenin, {Eliseo A.} and Berman, {Joan W.}",
year = "2012",
month = "8",
day = "18",
doi = "10.1186/1742-2094-9-203",
language = "English (US)",
volume = "9",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Characterization and function of the human macrophage dopaminergic system

T2 - Implications for CNS disease and drug abuse

AU - Gaskill, Peter J.

AU - Carvallo, Loreto

AU - Eugenin, Eliseo A.

AU - Berman, Joan W.

PY - 2012/8/18

Y1 - 2012/8/18

N2 - Background: Perivascular 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.Methods: To 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.Results: These 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.Conclusions: Monocyte 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.

AB - Background: Perivascular 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.Methods: To 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.Results: These 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.Conclusions: Monocyte 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.

KW - Aromatic amino acid decarboxylase

KW - Cytokine

KW - Dopamine

KW - Dopamine transporter

KW - Drug abuse

KW - Monocyte derived macrophage

KW - Neuroinflammation dopamine receptor

KW - Tyrosine hydroxylase

UR - http://www.scopus.com/inward/record.url?scp=84865053439&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865053439&partnerID=8YFLogxK

U2 - 10.1186/1742-2094-9-203

DO - 10.1186/1742-2094-9-203

M3 - Article

C2 - 22901451

AN - SCOPUS:84865053439

VL - 9

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

M1 - 203

ER -