The dopamine system in immunity: general information
Dopamine (DA) is known for its neurotransmitter function and, like other neurotransmitters, its effects are not limited to the central nervous system (CNS). Several studies support the idea that AD is a co-regulator of the immune system, tissues and organs. Alterations in the DA system have been associated with many health problems, including hypertension, psychiatric disorders (e.g. schizophrenia) and neurodegenerative diseases (e.g. Parkinson’s disease). The existence of DA in the blood suggests the presence of dopaminergic components that modulate the functions of the immune system. The effects of dopamine can be mediated by five types of cell receptors divided into type D1 (D1R and D5R) and type D2 (D2R, D3R and D4R). The expression of DRs was studied in all types of human leukocytes. Although their levels vary among human cell lines, among all leukocytes the expression of DR is lowest in T lymphocytes and monocytes, while B lymphocytes and NK cells carry the highest levels.
Human lymphocytes express D5R and two of its pseudogenes, ψD5DR-1 and ψD5DR-2, which are expressed but whose functions are unknown. Human peripheral blood lymphocytes also express D3R and D4R. The most recent studies show that DRD1 and D1R are expressed in stimulated T lymphocytes and are linked to the negative regulation of the immune response. The DA system has a specific plasma membrane transporter (SLC6A3 gene), called DAT. Other transporters also participate, such as the chromaffin granule amine transporter (VAT1 protein; SLC18A1 / VMAT1 gene) and the synaptic vesicular amine transporter (VAT2 protein; SLC18A2 / VMAT2 gene). DAT and VAT2 transporters are present in human peripheral blood lymphocyte membranes and the function and expression of DAT in white blood cells have been verified.
Effects of dopamine on white blood cells
Effects on peripheral granulocytes
Neutrophils are the most abundant white blood cell population and perform a significant function at the start of an inflammatory response. These cells contain intracellular catecholamines, such as DA, epinephrine and noradrenaline, and many of their metabolites, such as DOPAC, 3-MT, HVA, DHPG and metanephrine (MET). Furthermore, neutrophils synthesize and degrade these amines. Reserpine, a VAT1 inhibitor, reduces intracellular concentrations of DA and noradrenaline; while desipramine, a NET transporter inhibitor, reduces intracellular concentrations of norepinephrine. These findings imply the existence of catecholamine storage and reuptake mechanisms in neutrophils. Neutrophils express D3R and D5R receptors and, at lower densities, D2R and D4R, which allow AD to modulate their biological functions.
Neutrophils (from peripheral blood) that are incubated with DA reduce their phagocytic activity in a dose-dependent manner, such as the production of reactive oxygen species and chemotaxis. AD influences the viability of neutrophils from healthy volunteers and patients with systemic inflammatory response syndrome (SIRS). It induces their apoptotic death after 12 h of incubation in healthy volunteers and after 6 h in SIRS patients. The function of eosinophilic granuocytes in immunity is related to the response against parasites. These cells have a higher density of D3R and D5R receptors and a low density of D2R and D4R, while D1R is not detected. No studies have reported the effects of AD on eosinophils. Likewise, it is not known whether basophils, involved in the allergic response, express dopamine receptors or respond to dopamine.
Effects on monocytes / macrophages
Monocytes are found in peripheral blood and, upon entering the tissues, complete their differentiation into macrophages. Macrophages have a high phagocytic capacity towards microorganisms and dead cells, secrete large amounts of cytokines and present antigen in the context of MHC II. According to McKenna et al., human monocytes have a higher density of D2R and D3R than D4R and D5R. Dopamine modulates the phenotype and function of monocytes / macrophages. Stimulation of macrophages with D2 agonists (bromocriptine and quinpirol) appears to reduce the production of TNF-alpha, an inflammatory cytokine. This effect seems to depend on the D2 receptor, through which dopamine suppresses the activation of the nuclear factor NF-kB induced by the bacterial lipopolysaccharide. There are data that dopamine can modulate the viability of macrophages and the release of cytokines even in the absence of bacterial stimuli. At high concentrations, DA elevates cytokines such as CCL2, IL-6 and IL-10 while reducing TNF-alpha; at low concentrations only CXCL2 and IL-10 appear to be affected, indicating that plasma dopamine concentrations may influence the response to bacterial infections.
DA also has effects on macrophages with regards to HIV replication. This effect was observed in macrophages from healthy donors that were infected in vitro with the HIV strains and in Jurkat cells (T-cell derived line) that were transfected with the proviral HIV genome. Activation of D2R by the quinpirol agonist increases HIV replication in a dose-dependent manner, compared to unstimulated infected cells and cells stimulated with D1R agonists. In macrophages, the entry of HIV through CD4 and CCR5 into the plasma membrane depends on binding to the gp120 receptor, and an increase in the density of CCR5 and CD4 increases HIV infectivity. A recent study showed that dopamine facilitates the entry of HIV through the CCR5 receptor. These data suggest that virus entry requires activation of dopaminergic receptors and is inhibited by a global antagonist such as flupentixol, through effects that do not rely on viral concentration.
Effects on lymphocytes
At the end of the 20th century, it was shown that lymphocytes have the metabolic capacity to synthesize catecholamines and their metabolites; they also release and capture these molecules, responding to them by expressing catecholamine receptors. In the late 1990s, a rat study confirmed that lymph node, splenic and thymic lymphocytes contain intracellular catecholamines and tyrosine hydroxylase as rate-limiting enzymes. Furthermore, Ferrari and colleagues reported that DA modulates its synthesis in human T and B lymphocytes from peripheral blood. Searching for DA receptors in lymphocytes was a difficult task. Unstimulated human lymphocytes express D2R, D3R, D4R and D5R, but the activation of these cells changes the expression of the receptors. DA and DAT receptors, with the exception of D4R, have also been detected in B lymphocytes and in several malignant B cell lines (lymphomas); furthermore, this report showed higher DRD1 and DRD2 transcription levels than DRD3 and DRD4.
The immunomodulatory effects of AD have significant relevance in understanding the relationship between the immune system and the CNS. In 2001, Levita and colleagues suggested the importance of AD in integrin-mediated cell trafficking and extravasation of human T lymphocytes in the brain and periphery.They based on the findings that 7-hydroxy-DPAT (a D3R agonist), bromocriptine and pergolide (D2R agonists) activate T lymphocytes, upregulating the expression of integrins and increasing the adhesion of blood vessels to fibronectin. In 2005, Besser and colleagues demonstrated that resting human T lymphocytes express D2R, D3R and D5R on their membrane and that their stimulation upregulates the secretion and expression of cytokines, such as TNF-α and IL-10. Strell and colleagues demonstrated that human CD8 + T cells express D3R and D4R and, to a lesser extent, D5R. They also found that these receptors were downregulated during cellular activation, with the exception of D5R.
Stimulation with DA reduced the activation of these cells by anti-CD3 / CD28 antibodies, decreasing the expression and secretion of IL-2. This stimulation also interferes with the activation of the NF-kB factor. This effect prevents the creation of an autocrine cycle of IL-2, which is necessary for optimal activation of T lymphocytes. Other reports have shown that DA modulates lymphocyte activation, proliferation and differentiation in humans and rodents. In human cells, Bergquist and colleagues demonstrated that lectin-activated peripheral blood lymphocytes stimulated in vitro with DA slow their proliferation, differentiation, and IFN-γ synthesis. This group also reported that lectin-activated human lymphocytes stimulated with DA produce less IL-4 but experience 3-fold greater apoptosis. In other words, they suffer a higher turnover (elimination). This could be important in the context of autoimmunity that appears in reactive or chronic depressive syndromes.
If dopamine is constantly kept low during a chronic depressive event, there could be the loss described above of the restraining mechanisms on lymphocyte reactivity. If the self-reactive clones “perceive” this situation and it was just what they were waiting for, it can be understood why a severe trauma or a major depressive syndrome can lead to the onset of autoimmunity, as reported for autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis and even lupus. systemic in predisposed subjects.
Implications for autoimmune diseases
From a pathophysiological point of view, alterations in central AD levels affect lymphocyte function, as AD is supplied by the sympathetic nervous system to primary and secondary lymphoid tissues, modulating a wide range of immune activities, such as regulating the system. innate nervous immune and adaptive responses. Several studies have reported disturbances in the central production of AD in pathological conditions, the most common of which is Parkinson’s disease, characterized by the selective destruction of dopaminergic neurons in the substantia nigra. However, recent studies indicate that DA production and dopamine receptor expression are dysregulated in other neurodegenerative and autoimmune diseases, which has a significant impact on the immune response. Expression of dopaminergic receptors in lymphocytes of patients with neurodegenerative and autoimmune diseases has recently been proposed as a diagnostic biomarker and marker of disease severity, as the changes in the density of DA receptors on lymphocytes are usually similar to what is observed in the brain.
Immunomodulatory drugs, such as IFN-β, restore the functional reactivity of DRs on lymphocytes. Furthermore, IFN-β therapy appears to shift the balance of DR in lymphocytes from predominantly D2-like in untreated patient cells to predominantly D1-like. Upregulation of D1-like receptors is therefore expected to be beneficial in multiple sclerosis. Functional dysregulation of Treg contributes to the pathogenesis and activity of the disease in autoimmune mouse models of the CNS and in MS patients. Therefore, the use of dopamine agonists in MS could suppress Tregs lymphocytes via D1-type receptors, with harmful effects. In particular, IFN-β treatment downregulates D1-like receptors on Tregs and impedes the ability of dopamine to inhibit Treg function. These findings suggest that dopaminergic pathways in circulating lymphocytes have important immunomodulatory functions in MS pathology, influencing drug development for MS patients. Agonists have beneficial effects as an adjunct to immunomodulatory treatments with agents such as IFN-β, and may preferentially act on type D1 receptors rather than type D2 receptors.
In rheumatoid arthritis, synovial fibroblasts increase their expression of D1R and D5R. This disease has a high predominance of Th1 and Th17 lymphocytes; in addition, DA localizes in the synovial tissue of RA patients and significantly increases its levels in this fluid. The involvement of D2R in RA has been demonstrated in several mouse models. Its activation mitigates clinical symptoms, and mice without D2R protein develop severe RA symptoms. The D2R antagonists, on the other hand, induce the accumulation of IL-17 and IL-6 in the synovial fluid, aggravating the inflammatory process. Similarly, RA patients express low levels of D2R in lymphocytes, which is related to the severity of the disease. Based on this evidence, D2R agonists have been proposed as therapeutic agents for RA. Levels of D5R in B lymphocytes of patients with RA and osteoarthritis are lower than in healthy volunteers, while those of D2R and D3R are higher. Nakano and colleagues suggested that DA released by DC activates the IL-6-Th17 axis, aggravating synovial inflammation in the RA.
Therefore, clinical protocols have been developed in which clinical researchers should use D2R agonists, such as bromocriptine and cabergoline, to reduce prolactin synthesis and secretion by infiltrating synovial fibroblasts and lymphocytes in patients with RA. Finally, there are few data for systemic lupus erythematosus (SLE). It is known that in the peripheral white blood cells of patients with SLE, the D2R receptor is downregulated, while D4R increases compared to healthy subjects. Decreased D2R levels could be associated with decreased Treg cell function and number in this disease.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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