Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-
Dopamine (DA) is a monoamine that is best known for its neurotransmitter function, and like other neurotransmitters, its effects are not limited to the central nervous system (CNS). Several studies support the notion that DA is a coregulator of the immune system (IS) [
Based on the involvement of DA in behavioral and cognitive processes, many studies have focused on the nervous system [
The CNS and immune system are the main adaptive systems, participating in continuous and functional crosstalk to ensure homeostasis. DA and other catecholamines, such as noradrenaline, function as neuroimmunotransmitters in the sympathetic-adrenergic terminals of the autonomic nervous system, which innervates the primary and secondary lymphoid organs—in addition to the direct local effects that nonsynaptic varicosity secretions have on immune cells [
This review focuses on the function of the DAS in the immune system and the function of DA as an immunoregulatory molecule and on the communication between the CNS and IS, based mainly on studies in human cells. We also discuss the clinical aspects of disturbances in the DAS in mental disorders, such as schizophrenia, Parkinson disease, and other clinical conditions that are related to cancer, viral infections, and autoimmunity.
DA (3-hydroxytyramine; 3,4-dihydroxyphenethylamine; C8H11NO2) was first synthesized in 1910 [
In subsequent years, observations of small concentrations of DA in several peripheral tissues were reported. Curiously, the name “dopamine” was not adopted until 1952, when a shorter name was proposed by Henry Dale [
This difference, combined with results from other studies that used reserpine, an inhibitor of chromaffin granule amine transporter and synaptic vesicular amine transporter [
The idea of providing L-DOPA to patients with Parkinson disease and psychotic disorders arose soon thereafter, leading to the first clinical trials on L-DOPA to mitigate Parkinsonian symptoms [
Moreover, several studies already reported the relevance of DA as a modulator of motor function [
Arvid Carlsson, Paul Greengard, and Eric Kandel were awarded the Nobel Prize in Physiology or Medicine in 2000 for their work on signal transduction in the nervous system [
The DAS is a vast protein assembly that synthesizes, releases, senses, and metabolizes DA in various cell types in mammals. It also modulates a vast set of neuronal processes. Several examples of brain functions in which DA participates are cognition, motor control, mood, reward systems, pain perception, and sexual behavior [
The function of DA outside of the nervous system has only recently been studied. For instance, DA mediates
DA in peripheral systems originates from the nervous system and mesenteric region. The concentration of DA in peripheral plasma in humans is approximately 0.1 nmol/L (0.1 pmol/mL) and is derived primarily from sympathetic noradrenergic nerve fibers. This concentration can vary by up to nearly 50-fold for derivatives, such as DA sulfate, after ingestion of a standard meal and according to the region of the circulatory system [
The concentration of DA has been assessed in the mesenteric region in samples from abdominal surgeries for gastric adenocarcinoma and pancreatic neoplasm. Abdominal DA concentrations in arterial plasma (samples from the radial and hepatic arteries) and venous plasma (from the right hepatic and portal veins) are approximately 0.312 pmol/mL and 0.937 pmol/mL, respectively (estimated from Figure
The physiological mechanisms of the cell signaling and pharmacology of DRs and DA metabolism have been described extensively in the murine CNS [
The DAS has been observed in murine immune cells [
Dopaminergic proteins expressed in immune cells.
D1R | D2R | D3R | D4R | D5R | VAT1/2 | DAT | TH | DDC | D |
PAH | |
---|---|---|---|---|---|---|---|---|---|---|---|
Cellular types | T cell |
B cells |
B cells |
B cells |
B cells |
Immature dendritic cells |
Lymphocytes |
Lymphocytes |
HMDM (human monocyte-derived macrophages) [ |
T/B cells |
Leucocytes [ |
In the CNS, DA is synthesized through an anabolic pathway that is shared with other catecholamines, such as L-noradrenaline (NE) and adrenaline (E) [
In other tissues, such as the murine kidney, study of the relationship between DRs, oxidative stress, and the REDOX balance has provided information on high blood pressure [
A recent mathematical model of DA metabolism in Parkinson disease shows a certain degree of predictability with respect to pharmacological and genetic changes. The authors of this model propose its application
The classical pathway of DA synthesis begins with the production of L-tyrosine from L-phenylalanine by phenylalanine 4-hydroxylase (PAH) (EC: 1.14.16.1;
Metabolic pathways associated with DA. The metabolic pathways branching from the catabolism of L-phenylalanine are shown. (a) The dark blue arrows (over light yellow branches) indicate the DA generation pathway, and the red arrows (over light green branches) represent the noradrenaline and adrenaline pathway. Green arrows (over orange branches) show the alternative synthesis pathways to dopamine. The magenta arrows (over pink branches) show dopamine catabolism; the right side shows the normal pathways converging on HVA; the left side shows the catabolic pathways when dopamine concentrations are high in the cytoplasm. Many enzymes can transform dopamine and metabolites, such as COX enzymes (cyclooxygenases), producing dopaminochrome and dopamine quinone [
Two alternative pathways of DA synthesis have been identified in the rat brain and human hepatic microsomes. In the first mechanism, DDC transforms L-phenylalanine into phenylethylamine, which in turn is converted into tyramine by PAH; in the second pathway, DDC uses L-tyrosine to produce tyramine. In both cases, tyramine is converted into DA by the cytochrome p-450 CYP2D6 isoform (EC: 1.14.14.1;
The enzymatic activity of TH and PAH in human leukocytes has been detected since the 1980s [
In human lymphocytes, the presence and synthesis of certain catecholamines, such as L-DOPA and noradrenaline, the synthesis of which appears to be linked to cholinergic stimulation, have been measured, but they are differentially synthesized between B and T lymphocytes; L-DOPA exists in both cell types, but noradrenaline is only found in T cells [
In neurons, DA is recovered from the
Using DA, COMT produces 3-methoxytyramine (3MT), which MAO-A and MAO-B acquire to produce 3-methoxy-4-hydroxyacetaldehyde, which is then used by ALDH to generate
Other compounds have been detected by spontaneous oxidation of the catechol group of DA and L-DOPA by ROS and amino acids that are derived from cysteine. These compounds are the corresponding quinones, which are associated with oxidative stress, such as DOPA quinone, dopamine quinone, and 6-hydroxydopamine quinone. Beginning with these compounds, a series of oxidation steps with ROS and cysteines occur to generate thioester derivatives and cysteine adducts [
In the mesenteric system (the gastrointestinal tract, spleen, and pancreas), DOPA, DA, and DOPAC are metabolized in the kidneys, plasma, and primarily liver, increasing HVA levels in the portal vein [
Generally, the rise in certain metabolites from DA degradation might indicate that cells are damaged by oxidative stress, because when physiological DA concentrations are surpassed, the degradation catabolites (HVA, DOPAL, DOPAC, and 3MT) begin to generate reactive secondary catabolites through spontaneous oxidation by chemical interaction with ROS. Further, when the concentrations of all DA derivatives climb, other enzymes can use them as substrates to generate additional metabolites.
Most studies on DRs have been conducted in the CNS, but many reports in other tissues are being published. The human DAS comprises at least six membrane DRs: D1R, D2RL, D2RS, D3R, D4R, and D5R. D2DR has four isoforms that are generated by differential mRNA splicing and have varying functions and sizes. Whereas the two longer isoforms are 443 and 445 amino acids, the short isoforms have 29 and 31 fewer amino acids. The number of DRD3 and DRD4 isoforms has not been determined and is poorly documented in humans and animals [
Human lymphocytes express
Dopaminergic system protein components expressed in immune system.
Receptors of DRs | Genes names | References |
---|---|---|
D(1) receptor: D1R |
|
[ |
D(2) receptor longer: D2R |
|
[ |
D(3) receptor: D3R |
|
[ |
D(4) receptor: D4R |
|
[ |
D(5) receptor: D5R |
|
[ |
Sodium-dependent dopamine transporter: DAT |
|
[ |
|
||
Protein components shared with other monoamines systems | ||
Chromaffin granule amine transporter: VAT1 |
|
[ |
Synaptic vesicular amine transporter: VAT2 |
|
[ |
|
||
Protein components with unknown functions | ||
Chromaffin granule amine transporter: VAT1Δ15 |
|
[ |
|
|
[ |
|
|
[ |
Human peripheral blood lymphocytes also express
DRs belong to a superfamily of membrane proteins, called the
DRs are functionally classified into the
The activation of heterotrimeric G proteins is complex, because even if a DR has been classified by AC activation or inhibition, the specific proteins that constitute the heterotrimeric G protein complex are not accurately defined. This is evident when we consider the number of genes that encode for the G
The complexity of these interactions increases if we also consider that heterotrimeric G proteins are divided into two complementary signaling systems. For D2R in striatal medium spine neurons, the activation of G protein releases the G
The other transducer system that is coupled to DRs is the noncanonical G protein-independent,
The DAS has a plasma membrane-specific DA transporter (
VAT1 and VAT2, studied primarily in the brain, are general cytoplasmic amine transporter proteins that reside in the internal vesicular membranes of mammals [
DA is captured and transported to the interior of the cell by DAT, a Na+/Cl−-dependent DA transporter. Also, SERT (serotonin transporter) is able to take DA to the inside of the cell, though at low rates [
DAT and VAT2 transporters are present in the membranes of human peripheral blood lymphocytes [
Recently, the crystal structure of human DA D3R in complex with a D2R/D3R-specific antagonist, eticlopride, was solved at 2.89 Å resolution and deposited into Protein Data Bank under ID 3PBL [
The immune response is regulated by cytokines, hormones, and neurotransmitters; this regulation is possible because leukocytes have receptors for each one of these soluble factors (Table
The DRs effect on cytokine production.
Effect on cytokine production | Cellular types and stimuli | Receptors involved | References |
---|---|---|---|
|
HMDM + DA | D3R, D4R |
[ |
|
|||
|
HMDM + DA + LPS | D3R, D4R |
[ |
|
|||
|
Human activated T cells + quinpirole | D3R | [ |
|
|||
|
Human activated CD4 T cells + quinpirole | D3R | [ |
|
|||
|
Human activated CD8 T cells + quinpirole | D3R | [ |
|
|||
|
Rats T cells + L-DOPA + carbidopa | D3R | [ |
|
|||
|
D5RKO mice, mature bone marrow-derived dendritic cells + LPS | D5R absence | [ |
|
|||
|
Anti-CD3-stimulated human T cells + DA |
Not measured |
[ |
|
|||
|
Human CD4+ CD25+ regulatory T cells: |
(a) D2R, D3R, D4R |
[ |
|
|||
|
Mouse activated lymphocytes + L-DOPA |
Not measured | [ |
|
|||
|
Naive CD4+ T cells + DA | D1R/D5R | [ |
|
|||
|
Human resting NK cells + DA | D5R | [ |
|
|||
|
Human rIL-2 activated NK cells + DA |
D5R |
[ |
|
|||
|
Immature human Mo-Dc + L75066 |
D2- |
[ |
|
|||
|
T cells + DA |
D2R, D1- |
[ |
|
|||
|
Anti-CD3/CD28 stimulated T lymphocytes + PD168,077 | D4R | [ |
|
|||
|
Anti-CD3/CD28 activated Treg lymphocytes + DA |
Not measured | [ |
|
|||
|
Anti-CD3/CD28 activated T lymphocytes CD8+ + DA | Not measured | [ |
|
|||
|
Lymphocytes + DA | Not measured | [ |
|
|||
|
T cell (mesenteric lymph nodes) + ConA + SKF38393 |
D1- |
[ |
|
|||
|
Macrophages DAT |
DAT absence | [ |
Bone marrow (BM) is innervated by autonomic sympathoadrenergic efferent nerve fibers, in which the local microenvironment is critical in the maintenance of hematopoietic stem cells (HSCs). Stem cells are characterized by their capacity for self-renewal throughout the life of an individual and respond to signals that are generated in the microenvironment and identified by cell surface markers, such as CD34 and CD38 [
Maestroni and colleagues reported the first study on the functions of monoamines in hematopoiesis, performing chemical sympathectomy with 6-hydroxydopamine (6-OHDA) and observing a significantly higher peripheral blood leukocyte count in mice that underwent transplantation with BM [
Subsequently, Spiegel et al. demonstrated the expression of D3R and D5R in human CD34+ cells by flow cytometry. The more primitive CD34+CD3
Additional work of the function of DA demonstrated the amelioration of neutropenia and the restoration of the number of colony-forming unit-granulocyte macrophage (CFU-GM) colonies in the bone marrow of mice that were treated with 5-fluorouracil (5FU). These results are consistent with reports that have indicated that DA can be used safely as an antiangiogenic drug for malignant tumors [
Granulocytes are fundamental immune cells, based on their abundance and rapid activation in the presence of foreign elements. Granulocytes contain granules in their cytoplasm that harbor various inflammatory and antimicrobial mediators that effect their defensive activities. Depending on the content of their granules, these cells are classified in eosinophils, basophils, and neutrophils [
Eosinophil function in immunity is related to the response against parasites [
Neutrophils are the most abundant leukocyte population and have a significant function at the beginning of an inflammatory response [
Neutrophils express D3R and D5R DA receptors and, at lower densities, D2R and D4R [
DA also reduces the density of the adhesion molecules CD11b (Mac-1) and CD18 in neutrophils, decreasing endothelial adhesion. Even in neutrophils that have been stimulated with LPS or TNF-
Monocytes are found in peripheral blood, and on entering tissues, they complete their differentiation into macrophages. Macrophages have high phagocytic capacity toward microorganisms and dead cells, secrete large amounts of cytokines, and present antigen in the context of MHC II [
DA modulates the phenotype and function of monocytes/macrophages. An
In an elegant study, Gómez and colleagues reported that macrophages from guinea pigs that were immunized
Bergquist and colleagues examined whether the binding of NF-
Human monocyte-derived macrophages (HMDMs) from healthy donors express the
DA also has effects on macrophages with regard to D2R-mediated HIV replication. This effect has been observed in HMDMs of healthy donors that have been infected
In macrophages, the entry of HIV via CD4 and CCR5 in the plasma membrane depends on gp120 binding [
The average percentage of infected HMDMs rises with high concentrations of DA—between 10−5 and 10−8 M—dose-dependently, with a “
Dendritic cells (DCs) are the most efficient antigen-presenting cells of the immune system, with key functions in the induction of adaptive immune responses, immune tolerance, and the modulation of immune responses [
DA also has effects on murine bone marrow-derived dendritic cells (BMDCs), which express the molecular components that are needed to respond to, synthesize, store, and degrade DA. BMDCs bear D1R, D2R, D3R, and D5R on the membrane and vary their expression profile according to their state of activation: mature (stimulated by LPS) and immature (without stimulus). In the mature state, the intracellular enzyme TH, low levels of
In BMDCs, D5R appears to participate in maturation and regulate signaling pathways and cytokine release, thus contributing to the activation and proliferation of CD4+ T lymphocytes. BMDC activation with LPS significantly decreases the density of D5R in the membrane. On stimulation with SKF38393, a selective D1R/D2R agonist, the phosphorylation of ERK1/2 increases. Notably, D5R is linked to IL-12 and IL-23 production; it has been observed that mature
Lymphocytes are primordial cells of the adaptive immune response that recognize antigens in their molecular context. Depending on their ligands, lymphocytes have many subpopulations with a wide variety of functions; these cells can modulate, regulate, and coordinate the activities of other leukocyte populations through cytokine secretion and at the same time, lymphocytes can respond to circulatory levels of cytokines, hormones, and neurotransmitters [
In the late 20th century, lymphocytes were demonstrated to have the metabolic ability to synthesize catecholamines and their metabolites; they also release and recapture these molecules, responding to them by expressing catecholamine receptors. The initial reports on DA and DOPAC in lymphocytes were based on cerebrospinal fluid and human T and B lymphocyte cultures; these studies reported that intracellular catecholamine concentrations and the inhibition of TH with
Another study reported that human peripheral lymphocytes exhibit intracellular DA, L-DOPA, and NE at concentrations that are detectable by HPLC and that T lymphocytes only contain L-DOPA and NE.
In the late 1990s, a study in rats confirmed that lymph node, splenic, and thymic lymphocytes contain intracellular catecholamines (DA, NE, and E), observing
The first report on DAT in peripheral blood lymphocytes was performed using several techniques. By radiobinding assay (RBA) using a specific ligand for DAT, [3H]-GBR12935, it demonstrated specific binding in the membrane of human lymphocytes. By western blot, DAT, VAT1, and VAT2 were expressed, whereas DA and VAT2 showed immunoreactivity in cytoplasmic areas, corresponding to vacuoles, by immunofluorescence. Finally, DAT and VAT1 were detected in the plasma membrane and cytoplasm, respectively [
The search for DA receptors in lymphocyte has been a difficult task. Unstimulated human lymphocytes express D2R, D3R, D4R, and D5R, but the activation of these cells modifies the expression of the receptors. In 1991, the initial data on specific dopamine binding sites in human lymphocytes were obtained using [3H]-DA, the binding of which declines considerably in the presence of such substances as cocaine and other inhibitors of biogenic amine uptake [
Another study with [3H]-sulpiride in human lymphocytes by RBA characterized the D2-
In 1998, Ricci and colleagues measured the expression in membrane-bound D2-
In 2002, McKenna et al. performed flow cytometry to confirm the membrane expression of the three D2-
The immunomodulatory effects of DA have significant relevance in understanding the relationship between the immune system and CNS. Reports in rodent and human lymphocytes have found that DA receptors in PBMCs are functional and activate signaling cascades that change the phenotype and function of lymphocytes. Some groups have reported the effects of DA on cytokine secretion, cell adhesion, and chemotaxis in human and rodent lymphocytes.
In 2001, Levite and colleagues suggested the importance of DA in integrin-mediated cellular trafficking and extravasation of human T lymphocytes in the brain and periphery, based on findings that 7-hydroxy-DPAT (a D3R agonist), bromocriptine, and pergolide (D2R agonists) activate T lymphocytes, upregulating
Watanabe and colleagues showed that CD8+ T lymphocytes selectively express D3R and that its stimulation mediates chemotaxis and CD8+ T lymphocyte adhesion. DA and its agonist, 7-OH-DPAT (100 nM), increase CD45RA+ CD8+ naive T lymphocyte chemotaxis, whereas the combination of DA and other chemokines enhances chemotaxis in CD45RA+ CD4+ and CD45RA+ CD8+ T lymphocytes. Stimulation with only CCL19 (10 nM), CCL21 (10 nM), and CXCL12 (0.1 nM) significantly induces the migration of CD4+ and CD8+ lymphocytes, but the addition of DA (1 nM) induces the selective migration of CD45RA+CD8+ T lymphocytes. In addition, D3R stimulation induces the adhesion of CD45RA+ CD8+ T and CD45RO+ CD8+ T lymphocytes to FN [
With regard to animal models, Kipnis and colleagues showed that DA regulates the adhesion and chemotaxis of mouse Treg lymphocytes by stimulating D1-
Watanabe and colleagues showed by
Other reports have shown that DA modulates the activation, proliferation, and differentiation of lymphocytes in humans and rodents. In human cells, Bergquist and colleagues showed that ConA-activated peripheral blood lymphocytes stimulated
In 2001, Saha and colleagues demonstrated that high DA concentrations in serum affect the proliferation of CD4+ and CD8+ T lymphocytes and the cytotoxicity of lymphocyte activated killer T cells (LAK-Ts) from patients with lung carcinoma and healthy subjects. The patients had high DA concentrations in plasma compared with healthy subjects (
Ghosh and colleagues reported that DA also affects TCR-mediated signaling in T lymphocytes. Incubation with DA at 3–5 ng/mL for 1 to 3 days inhibited the proliferation and secretion of IL-2, IFN-
Studies in rodent cells
In 2011, a study reported that stimulation of D1-
Bergquist and colleagues reported that, at high concentrations (100–500
DA also has indirect effects on the phenotype and function of lymphocytes. This catecholamine first modulates the function of its target cell, which in turn affects the function and phenotype of the lymphocyte with which it interacts; these effects on human cells have been described by other groups.
In 2007, Cosentino and colleagues demonstrated that DA is released by Treg, allowing them to regulate their activity. However, when Treg do not release DA, they experience autoregulation and lose the ability to suppress Teff proliferation. CD4+CD25− Teff and CD4+CD25+ Treg from healthy donors express the five DA receptors. Treg have detectable mRNA levels of
A 2004 study by Kipnis et al. in mice showed that Treg from splenic lymph nodes had lower regulatory activity on stimulation of D1-
Mori and colleagues reported that D1-
Ilani and colleagues hypothesized that dopaminergic activation of blasts (cells that cross the blood-brain barrier) induces the Th1 phenotype and effects changes in membrane surface markers. The authors suggest that these alterations are transferred from blasts to peripheral resting T lymphocytes by neurotransmitter-mediated brain regulation of peripheral T lymphocytes. In this work, blast formation was induced from peripheral blood lymphocytes of healthy donors (cells that have been activated with mitogen and IL-2 that express VLA-4 on their membrane); these blasts were incubated with the D2R/D3R agonist quinpirole (10−5 M–10−7 M) for 8 hours. Quinpirole downregulates
Further, this group noted differential responses between CD4+ and CD8+ blasts. CD4+ blasts had lower
In resting T lymphocytes, incubation with blast supernatant for 24 hours without quinpirole increased
NK cells constitute less than 10% of all circulating lymphocytes and have significant functions in the immune response against viruses, intracellular bacteria and in tumor cell destruction [
There are differences in the phenotype and function of human and murine NK cells—human NK cells express membrane D2R, D3R, D4R, and D5R but lack D1R [
Central and peripheral DA can directly or indirectly regulate the immune system in several pathological conditions, such as neurodegenerative (Parkinson disease, Alzheimer disease, and Lesch-Nyhan syndrome), psychiatric (schizophrenia), and immune diseases (multiple sclerosis, encephalomyelitis, and rheumatoid arthritis, among others), and conditions that have an addictive component, such as alcoholism.
In terms of a physiopathological perspective, disturbances in the levels of central DA affect the function of lymphocytes, because DA is supplied by the sympathetic nervous system to primary and secondary lymphoid tissues, modulating a wide range of immune activities, such as the regulation of innate immune and adaptive responses [
The expression of dopaminergic receptors in lymphocytes from patients with neurodegenerative and autoimmune diseases has recently been proposed as a diagnostic biomarker and a marker of pathological severity, because the variations in the density of DA receptors on lymphocytes are usually similar to what is observed in the brain. In this section, we catalog the evidence on variations in the expression of DRs on lymphocytes in various pathologies (Table
Pathology-associated dopaminergic protein expression in immune cells.
Pathology/condition | DA receptors and cell types involved | Reference |
---|---|---|
Parkinson disease |
|
[ |
|
||
Lesch-Nyhan disease |
|
[ |
|
||
Multiple sclerosis |
|
[ |
|
||
Multiple sclerosis treatment with IFN- |
|
[ |
|
||
Schizophrenia |
|
[ |
|
||
Rheumatoid arthritis |
|
[ |
|
||
Rheumatoid arthritis and |
|
[ |
|
||
Systemic lupus erythematosus |
|
[ |
|
||
Alcohol dependence syndrome |
|
[ |
|
||
Alcohol withdrawal |
|
[ |
|
||
Computer game addicts |
|
[ |
Changes in activation of the immune response in patients and in experimental models of neurodegenerative diseases have been described and implicated in their pathogenesis. Abnormalities in the number and function of circulating lymphocytes are linked to an increase in the production of proinflammatory mediators. The evidence in this section strongly suggests that the DAS participates in the modulation of the immune response.
Parkinson disease is a neurodegenerative pathology that is characterized by the dysfunction and degeneration of dopaminergic neurons in the substantia nigra, neuroinflammation, and motor disturbances. In animal models in which the selective loss of dopaminergic neurons from the substantia nigra is induced by systematic administration of methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), significant changes in the immune response have been observed. For example, proinflammatory cytokines, such as IFN-
Regulation by the central DAS modifies peripheral immune functions. For instance, MPTP-induced depletion of DA in the striatum promotes tumor growth, which is associated with dysfunctional cytotoxic activity in T lymphocytes and NK cells [
Some studies propose that the activation of circulating lymphocytes is able to regulate the neurodegenerative events in the substantia nigra in Parkinson disease. The stimulation of D3R in CD4+ T lymphocytes decreases their synthesis of IL-4 and IL-10 while promoting IFN-
Similarly,
Patients with a likely diagnosis of Alzheimer disease have a low density of D2-
Studies have reported changes in the expression of DRs in lymphocytes in various pathologies of the CNS. Lesch-Nyhan syndrome is a neurogenetic disorder that is caused by the complete deficiency of hypoxanthine-guanine phosphoribosyltransferase, which effects severe motor disturbances, predominantly dystonia (numbness) and occasionally chorea (involuntary movements); these secondary symptoms are related to disturbances in the production of DA in the CNS. Lesch-Nyhan syndrome patients have higher levels of
Studies on disturbances in the DAS in schizophrenia patients have reported changes in the expression of DA receptors. In the 1980s, a study examined the binding of [3H]-spiperone, a specific dopaminergic antagonist, to peripheral blood lymphocytes from healthy volunteers, 27 patients with acute schizophrenia under no treatment, and 16 psychiatric patients as a control group by RBA. The study did not find any differences in binding parameters between the healthy and psychiatric control groups, whereas the binding of [3H]-spiperone increased significantly in lymphocytes from schizophrenia patients with a slight decrease in affinity [
At the beginning of the 21st century, Kwak and colleagues performed an 8-week longitudinal study to measure D3R and D5R expression in peripheral blood lymphocytes from 44 patients who had been treated pharmacologically for over three years, 15 drug-naive schizophrenic patients, 28 drug-free patients, and healthy controls.
In 2006, Boneberg and colleagues measured DA receptor (D1R–D4R) expression in neutrophils, monocytes, B lymphocytes, NK cells, and CD4+ and CD8+ lymphocytes from 10 schizophrenic patients, reporting a significant increase in
Another study attempted to identify schizophrenia markers in peripheral blood lymphocytes from 13 drug-naive/drug-free patients. In a microarray analysis,
Recently, Brito-Melo and colleagues used flow cytometry to measure membrane expression of D2R, D4R, and serotonin receptors in CD4+ and CD8+ peripheral blood T lymphocytes from schizophrenic patients who had been treated pharmacologically for ten years. They correlated these levels with several clinimetric scales: Brief Psychiatric Rating (BPRS), Positive and Negative Syndrome (PANSS), and Involuntary Movement (AIMS). The group observed significant overexpression of D4R in CD8+ and CD4+ T lymphocytes from schizophrenic patients and upregulation of D2R in CD8+ T lymphocytes; in contrast, D2R levels were lower in CD4+ T lymphocytes. Further, BPRS and PANSS scores correlated with CD8+D2R+ lymphocyte levels, and AIMS scores were positively associated with CD4+D2R+ T lymphocytes levels and inversely related to CD4+D4R+ T levels [
In 2013, Liu and colleagues measured
Another study analyzed the
Multiple sclerosis (MS) is the most common immune-mediated demyelinating disease of the CNS. This condition causes disability in 2.3 million people worldwide. In MS, myelin-reactive CD4+ Th lymphocytes enter the CNS, where they interact with resident cells, promoting inflammation, demyelination, and neurodegeneration [
The typical treatment for MS is IFN-
In untreated patients, the expression and activity of D1-
Functional dysregulation of Treg contributes to disease pathogenesis and activity in autoimmune mouse models of the CNS and in patients with MS. Thus, the use of DR agonists in MS might suppress Treg via D1-
These findings suggest that the dopaminergic pathways in circulating lymphocytes have relevant immunomodulatory functions in the pathology of MS, impacting the development of drugs for patients with MS—DR agonists have beneficial effects as an add-on to immunomodulatory treatments with such agents as IFN-
Experimental autoimmune encephalomyelitis (EAE) is an experimental model of human MS. Balkowiec-iskta and colleagues showed that injury to the dopaminergic system modulates the clinical course and inflammatory reaction during EAE; this group studied the effects of dopamine depletion with 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) in C57BL mice with EAE (induced by the MOG 35–55 peptide). They found that MPTP decreased striatal DA levels, and the mean number of inflammatory cells in the spinal cord infiltrate was significantly higher in MPTP + MOG 35–55-treated versus MOG 35–55-treated mice. The mortality rate in mice with a dysfunctional dopaminergic system was lower than in MOG 35–55-treated mice. Also,
Nakano et al. showed that antagonizing D1-
Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by pannus tissue, consisting of synovial fibroblasts (SFs), macrophages, and lymphocytes. The inflammatory milieu in the joint activates resident SFs and transforms them [
The involvement of D2R in RA has been demonstrated in several murine models. Its activation mitigates clinical symptoms, and
D5R levels in B lymphocytes from RA and osteoarthritis patients are lower than in healthy volunteers, whereas those of D2R and D3R are higher [
Systemic lupus erythematosus is an autoimmune disease that is characterized by the dysfunction of several organs, including the liver and brain, due to a dysregulated immune system. In PBMCs of systemic lupus erythematosus patients,
Glomerulonephritis encompasses a range of immune-mediated disorders that cause inflammation in the glomerulus and other compartments of the kidney [
In another study by Hoeger et al. using the same brain-dead model in rats, the changes in cytokine and chemokine expression were measured to determine the mechanism by which DA lowers renal inflammation. This study evaluated the expression of IL-6, IL-10, macrophage chemoattractant protein 1 (MCP-1), and cytokine-induced neutrophil chemoattractant 1 (CINC-1), a rat homolog of IL-8. No significant changes were observed in IL-6, IL-10, and MCP-1, but CINC-1 was significantly downregulated in the brain-dead animal group that was treated with DA compared with controls, implicating this change as an anti-inflammatory mechanism that is induced by DA during renal inflammation [
The dopaminergic system has garnered significant interest in angiogenesis and tumor immunity. Endothelial cells express components of the dopaminergic system; thus, DA governs angiogenesis, prompting an examination of the molecular mechanisms that are associated with modulation of tumor immunity, its mechanisms of control, and the link between tumor immunity and angiogenesis [
In a murine model, the antitumor effects of DA on Ehrlich ascites carcinoma cells already have been reported [
The low incidence of certain types of cancer in schizophrenic patients, in contrast with the high incidence in patients with Parkinson disease, reflects the inhibitory effects of DA on cancer cell growth. This hypothesis is based on the finding that schizophrenic patients express a hyperdopaminergic system, whereas Parkinson patients are hypodopaminergic. However, it is unknown if disruptions in the dopaminergic system in the CNS contribute to the development of tumor angiogenesis outside of the CNS [
Conversely, DA selectively inhibits vascular permeability and the angiogenic activity of VEGF. This inhibitory effect is mediated by the activation of D2R and the induction of the endocytosis of VEGFR-2 [
Another study demonstrated that DA acts through D2R to inhibit the proliferation of gastric cancer cells that have been induced by insulin-like growth factor receptor-I (IGF-IR). This inhibition is mediated by the upregulation of Krüppel-like factor 4 (KLF4) [
The relationship between DA, transformed cells, and the immune system is unknown, but it is likely that a link exists with mechanisms of the identification and elimination of abnormal cells, because DA inhibits tumor angiogenesis and stimulates tumor immunity; nevertheless, more studies are needed to examine this issue.
The involvement and significance of DA as a neurotransmitter and immunomodulator have been studied, but its effects on glucose homeostasis and pancreatic
DA and its derivatives can act directly in pancreas; the networks between the CNS and pancreatic islets are based on the central vagal connection through the parahypothalamic ventricular nucleus [
Insulin production depends on the concentration of DA [
One regulatory mechanism that explains the effects of DA states that DA in pancreatic
The effects of DA on the immune system in this disease are not well elucidated. One study showed that the D1-
Diabetes mellitus is a disease with an important inflammatory component; understanding the regulation of DA in the immune system and the significance of the inflammatory condition in the development of this disease will require a more detailed examination of the regulation of DA in this condition with regard to immunity.
The function of the D1R and D2R receptors in the brain is linked to the reward system and might be affected by extended drug use. Several reports indicate that the expression of DRs in immune system cells is altered during addiction. For instance, in patients who suffer from alcohol dependence,
Similarly, opioid addicts experience an increase in
Based on the activity of DA as a neurotransmitter, studies on the DAS have focused primarily on the CNS. Recently, however, copious experimental evidence indicates that the DAS has important physiological functions in the immune system. The human DAS is complex and comprises many elements; leukocytes have frequently been demonstrated to synthesize, release, perform reuptake of, and metabolize DA. In certain cases, as in Treg cells, DA is released to elicit autocrine effects, implicating the existence of a peripheral DAS that is independent of the CNS.
In this review, we have discussed the immunomodulatory effects of DA by activating DRs, which are differentially expressed in leukocytes, depending on cell type, activation state, DA concentration, and duration of exposure to DA. These effects regulate many cellular processes, such as cell activation, cell adhesion, proliferation, respiratory burst, chemotaxis, apoptosis, cytotoxicity, and cytokine and antibody secretion, and several changes at the phenotypic level and function in certain cell types. All of this activity is linked to the intracellular concentration of cAMP and the activation status of second messengers and transcription factors.
The information that we have here is based on existing reports, but the effects of DA on the immune system require further characterization. The peripheral DAS is dysregulated in patients with psychiatric disorders, neurodegenerative diseases, and other conditions, such as multiple sclerosis. However, more research is needed to demonstrate that peripheral disturbances in the DAS are equivalent to those in the CNS, which will facilitate the identification and characterization of new peripheral biomarkers for diagnostic purposes and the evaluation of the therapeutic efficacy of pharmacological treatments in these illnesses.
The authors declare no competing interests with regard to this paper.
Rodrigo Arreola, Samantha Alvarez-Herrera, Gilberto Pérez-Sánchez, Enrique Becerril-Villanueva, Carlos Cruz-Fuentes, Enrique Octavio Flores-Gutierrez, María Eugenia Garcés-Alvarez, Dora Luz de la Cruz-Aguilera, Emilio Medina-Rivero, Gabriela Hurtado-Alvarado, Saray Quintero-Fabián, and Lenin Pavón drafted the paper. All authors reviewed the paper and approved the final version.
This work was supported in part by Instituto Nacional de Psiquiatria “Ramón de la Fuente” Project NC-15-0048; SC-15-2414; SECITI-CM-48/14-SECITI/067/2015; Proyecto Factor de Transferencia-IPN: IC-10-002; PRODEP 14412732; and Universidad Nacional Autonoma de México; Programa de Doctorado en Ciencias Biomédicas, CONACYT.