Dopamine, Immunity, and Disease.

The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.

Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity.

BACKGROUND: Recent evidence has shown dopamine as a major regulator of inflammation. Accordingly, dopaminergic regulation of immune cells plays an important role in the physiopathology of inflammatory disorders. Multiple sclerosis (MS) is an inflammatory disease involving a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Evidence from animal models has suggested that B cells play a fundamental role as antigen-presenting cells (APC) re-stimulating CD4+ T cells in the CNS as well as regulating T-cell response by mean of inflammatory or anti-inflammatory cytokines. Here, we addressed the role of the dopamine receptor D3 (DRD3), which displays the highest affinity for dopamine, in B cells in animal models of MS. METHODS: Mice harbouring Drd3-deficient or Drd3-sufficient B cells were generated by bone marrow transplantation into recipient mice devoid of B cells. In these mice, we compared the development of experimental autoimmune encephalomyelitis (EAE) induced by immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (pMOG), a model that leads to CNS-autoimmunity irrespective of the APC-function of B cells, or by immunization with full-length human MOG protein (huMOG), a model in which antigen-specific activated B cells display a fundamental APC-function in the CNS. APC-function was assessed in vitro by pulsing B cells with huMOG-coated beads and then co-culturing with MOG-specific T cells. RESULTS: Our data show that the selective Drd3 deficiency in B cells abolishes the disease development in the huMOG-induced EAE model. Mechanistic analysis indicates that although DRD3-signalling did not affect the APC-function of B cells, DRD3 favours the CNS-tropism in a subset of pro-inflammatory B cells in the huMOG-induced EAE model, an effect that was associated with higher CXCR3 expression. Conversely, the results show that the selective Drd3 deficiency in B cells exacerbates the disease severity in the pMOG-induced EAE model. Further analysis shows that DRD3-stimulation increased the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in the pMOG-induced EAE model. CONCLUSIONS: Our findings demonstrate that DRD3 in B cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B cells with APC-function and promoting CNS-homing of B cells with anti-inflammatory features. Thus, these results show DRD3-signalling in B cells as a critical regulator of CNS-autoimmunity.

Dopaminergic Receptor Targeting in Multiple Sclerosis: Is There Therapeutic Potential?

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.

Electroacupuncture alleviates intestinal inflammation and barrier dysfunction by activating dopamine in a rat model of intestinal ischaemia.

BACKGROUND: To investigate whether the mechanism underlying the anti-inflammatory effects of electroacupuncture (EA) at ST36 involves dopamine (DA) and its receptor and whether it is mediated by the vagus nerve in a rat model of intestinal ischaemia-reperfusion (I/R) injury. METHODS: Rats were subjected to gut ischaemia for 30 min and then received EA for 30 min with or without abdominal vagotomy or intraperitoneal administration of butaclamol (D1 receptor antagonist) or spiperone (D2 receptor antagonist). Plasma levels of DA and tumour necrosis factor (TNF)-α were assessed 1 or 4 h after reperfusion. Myeloperoxidase (MPO) activity and malondialdehyde (MDA) content in intestinal tissues were assessed using enzyme-linked immunosorbent assay (ELISA) kits. Intestinal tissue injury was assessed by observation of the pathological lesions and permeability to 4 kDa fluorescein isothiocyanate (FITC)-dextran. RESULTS: EA significantly increased levels of DA and lowered levels of TNF-α. EA also inhibited intestinal levels of MPO and MDA and intestinal tissue injury and decreased intestinal permeability to FITC-dextran. Abdominal vagotomy and intraperitoneal administration of butaclamol (but not spiperone) inhibited the effects of EA. CONCLUSION: These findings suggest that EA at ST36 could attenuate intestinal I/R-induced inflammatory injury and that the underlying mechanism may involve EA-induced increases in levels of DA, mediated by the vagus nerve and D1 receptors.

A trade-off switch of two immunological memories in Caenorhabditis elegans reinfected by bacterial pathogens.

Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories.

Effect of Anti-Glutamate Antibodies in Modeled Parkinsonian Syndrome.

We studied the effect of single and repeated intranasal administration of antibodies to glutamate in experimental parkinsonian syndrome induced by injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6J mice. Intranasal administration of anti-glutamate antibodies to mice in parallel with administration of MPTP over 10 days alleviated parkinsonian symptoms (oligokinesia and rigidity). In the serum of mice injected with antibodies to glutamate and/or MPTP, the titers of autoantibodies to glutamate and dopamine were higher than in control animals receiving saline. Single intranasal administration of anti-glutamate antibodies to mice with established parkinsonian syndrome did not affect the severity of parkinsonian symptoms.

Dopaminergic and Adrenergic Pathways as Targets for Drug Repurposing in the Neuroimmune Network.

Dopamine, noradrenaline and adrenaline are catecholamines, and are all produced along the same metabolic pathway. Their discovery dates back to the early 1900s, and they were appreciated until the second half of the century mainly for their role in the brain and in the regulation of autonomic functions. Nonetheless, in the 1970s characterization of the key role of sympathoadrenergic nerve fibers in the cross-talk between the brain and the immune system paved the way to the raise of modern neuroimmunology, and understanding the immune effects of dopamine occurred in the subsequent decades. Both adrenergic and dopaminergic transmission offer a possibly unparalleled wealth of therapeutic targets, and most of them have been already successfully exploited for cardiovascular, respiratory, neurologic and even psychiatric diseases, however so far the therapeutic potential of adrenergic and dopaminergic agents in the neuroimmune network remains relatively unexploited. This special issue provides a unique collection of expert contributions from some of the most prominent researchers currently studying dopaminergic and adrenergic agents in major diseases like cancer, autoimmunity, neurodegeneration, and even in emerging areas like hematology and metabolism. It is strongly hoped that these reviews will be not only helpful for researchers already working on topics related to the neuroimmune pharmacology of catecholamines, but will also attract novel researchers as much work is still needed to fully exploit the therapeutic potential of dopaminergic and adrenergic drugs for the benefit of patients.

Targeting the Dopaminergic System in Autoimmunity.

Dopamine has emerged as a fundamental regulator of inflammation. In this regard, it has been shown that dopaminergic signalling pathways are key players promoting homeostasis between the central nervous system and the immune system. Dysregulation in the dopaminergic system affects both innate and adaptive immunity, contributing to the development of numerous autoimmune and inflammatory pathologies. This makes dopamine receptors interesting therapeutic targets for either the development of new treatments or repurposing of already available pharmacological drugs. Dopamine receptors are broadly expressed on different immune cells with multifunctional effects depending on the dopamine concentration available and the pattern of expression of five dopamine receptors displaying different affinities for dopamine. Thus, impaired dopaminergic signalling through different dopamine receptors may result in altered behaviour of immunity, contributing to the development and progression of autoimmune pathologies. In this review we discuss the current evidence involving the dopaminergic system in inflammatory bowel disease, multiple sclerosis and Parkinson's disease. In addition, we summarise and analyse the therapeutic approaches designed to attenuate disease development and progression by targeting the dopaminergic system. Graphical Abstract Targetting the dopaminergic system in autoimmunity. Effector T-cells (Teff) orchestrate inflamamtion involved in autoimmunity, whilst regulatory T-cells (Tregs) suppress Teff activity promoting tolerance to self-constituents. Dopamine has emerged as a key regulator of Teff and Tregs function, thereby dopamine receptors have becoming important therapeutic targets in autoimmune disorders, especially in those affecting the brain and the gut, where dopamine levels strongly change with inflammation.

Dopaminergic Agents in Rheumatoid Arthritis.

Clinical evidences suggest a causal relationship between rheumatoid arthritis (RA) and the dopaminergic system, and several studies described an alteration of the disease in patients treated with dopaminergic agents. Despite these interesting results, potential direct effects of dopamine on RA have not been intensively considered until the last decade. Recent studies confirm a direct effect of dopamine on the systemic immune response as well as on bone remodeling and on joint inflammation, both in humans and in different animal models of arthritis. While more research is necessary to accurately determine the effect of dopamine in RA, these results are encouraging and support a possible use of dopaminergic drugs for the treatment of arthritis in the future. Moreover, they point out that dopaminergic agents use to treat comorbidities, might influence the immune response and the disease progression in RA patients. This review summarizes the current knowledge about the effects of dopaminergic drugs on RA and describes the potential of dopaminergic drugs as future therapeutic strategy in arthritis. Graphical Abstract.

Where Is Dopamine and how do Immune Cells See it?: Dopamine-Mediated Immune Cell Function in Health and Disease.

Dopamine is well recognized as a neurotransmitter in the brain, and regulates critical functions in a variety of peripheral systems. Growing research has also shown that dopamine acts as an important regulator of immune function. Many immune cells express dopamine receptors and other dopamine related proteins, enabling them to actively respond to dopamine and suggesting that dopaminergic immunoregulation is an important part of proper immune function. A detailed understanding of the physiological concentrations of dopamine in specific regions of the human body, particularly in peripheral systems, is critical to the development of hypotheses and experiments examining the effects of physiologically relevant dopamine concentrations on immune cells. Unfortunately, the dopamine concentrations to which these immune cells would be exposed in different anatomical regions are not clear. To address this issue, this comprehensive review details the current information regarding concentrations of dopamine found in both the central nervous system and in many regions of the periphery. In addition, we discuss the immune cells present in each region, and how these could interact with dopamine in each compartment described. Finally, the review briefly addresses how changes in these dopamine concentrations could influence immune cell dysfunction in several disease states including Parkinson's disease, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, as well as the collection of pathologies, cognitive and motor symptoms associated with HIV infection in the central nervous system, known as NeuroHIV. These data will improve our understanding of the interactions between the dopaminergic and immune systems during both homeostatic function and in disease, clarify the effects of existing dopaminergic drugs and promote the creation of new therapeutic strategies based on manipulating immune function through dopaminergic signaling. Graphical Abstract.

Dopaminergic Pathways in Obesity-Associated Inflammation.

The overwhelming prevalence of obesity is a priority for public health compromising human lifespan and representing important economic burden worldwide. Obesity is characterized by a state of chronic low-grade inflammation associated to metabolic dysfunction. Although the efforts for unravelling the complex immunometabolic signaling pathways to explain the association of obesity with type 2 diabetes, cardiovascular diseases, cancer, neurodegenerative diseases and psychiatric disorders, we still do not have all the picture to design effective therapeutic to fight these immunometabolic disease clusters. Dopaminergic pathways apart from having a major role in the regulation of appetite and feeding behaviors are important immunoregulators in inflammation; thus, dopaminergic regulation is suggested to impact obesity- associated inflammation. Dopamine (DA) has been reported to modulate immune function and immune cells themselves produce endogenous DA. DA-induced immunomodulation is currently the focus of intense experimental research and dopaminergic pathways are increasingly considered a target for drug development in immune diseases. While the role of dopaminergic pathways in immune-mediated diseases has been intensively investigated in neurodegenerative diseases, dopaminergic immunomodulation in obesity-associated inflammation is largely unknown. This review will integrate the actual knowledge about dopaminergic pathways involved in obesity-associated inflammation with special focus on immune innate key cell players. We present an explanatory hypothesis with a model that integrate central and peripheral dopaminergic circuits in the relationship between neuroimmune and metabolic systems in obesity-associated inflammation. A perspective on the potential role of dopaminergic drugs in the context of obesity will be given. Graphical Abstract Graphical representation of central and peripheral dopaminergic pathways in obesity-associated inflammation.

Dopaminergic Therapeutics in Multiple Sclerosis: Focus on Th17-Cell Functions.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with an autoimmune mechanism of development. Currently, one of the most promising directions in the study of MS pathogenesis are the neuroimmune interactions. Dopamine is one of the key neurotransmitters in CNS. Furthermore, dopamine is a direct mediator of interactions between the immune and nervous systems and can influence MS pathogenesis by modulating immune cells activity and cytokine production. Recent studies have shown that dopamine can enhance or inhibit the functions of innate and adaptive immune system, depending on the activation of different dopaminergic receptors, and can therefore influence the course of experimental autoimmune encephalomyelitis (EAE) and MS. In this review, we discuss putative dopaminergic therapeutics in EAE and MS with focus on Th17-cells, which are thought to play crucial role in MS pathogenesis. We suggest that targeting dopaminergic receptors could be explored as a new kind of disease-modifying treatment of MS. Graphical Abstract.

The Functional Significance of Endocrine-immune Interactions in Health and Disease.

Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.

T cell addiction: can pathogenic T cells be controlled using dopamine receptors?

Crosstalk between the immune system and the nervous system, via neurotransmitters such as dopamine, is increasingly of interest as we begin to learn how lymphocytes in peripheral tissues can both produce and respond to these molecules. This crosstalk can modulate immune responses by influencing the local tissue environment and can, for instance, influence the activation status and migration of T cells. Immune cells also use neurotransmitters to communicate with each other. Understanding how neurotransmitters influence the immune system may provide novel approaches for targeting diseases associated with tissue-specific inflammation, such as psoriasis.

IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease.

Neuroinflammation has been involved in pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disease characterized neuropathologically by progressive dopaminergic neuronal loss in the substantia nigra (SN). We recently have shown that helper T (Th)17 cells facilitate dopaminergic neuronal loss in vitro. Herein, we demonstrated that interleukin (IL)-17A, a proinflammatory cytokine produced mainly by Th17 cells, contributed to PD pathogenesis depending on microglia. Mouse and rat models for PD were prepared by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or striatal injection of 1-methyl-4-phenylpyridinium (MPP+), respectively. Both in MPTP-treated mice and MPP+-treated rats, blood-brain barrier (BBB) was disrupted and IL-17A level increased in the SN but not in cortex. Effector T (Teff) cells that were adoptively transferred via tail veins infiltrated into the brain of PD mice but not into that of normal mice. The Teff cell transfer aggravated nigrostriatal dopaminergic neurodegeneration, microglial activation and motor impairment. Contrarily, IL-17A deficiency alleviated BBB disruption, dopaminergic neurodegeneration, microglial activation and motor impairment. Anti-IL-17A-neutralizing antibody that was injected into lateral cerebral ventricle in PD rats ameliorated the manifestations mentioned above. IL-17A activated microglia but did not directly affect dopaminergic neuronal survival in vitro. IL-17A exacerbated dopaminergic neuronal loss only in the presence of microglia, and silencing IL-17A receptor gene in microglia abolished the IL-17A effect. IL-17A-treated microglial medium that contained higher concentration of tumor necrosis factor (TNF)-α facilitated dopaminergic neuronal death. Further, TNF-α-neutralizing antibody attenuated MPP+-induced neurotoxicity. The findings suggest that IL-17A accelerates neurodegeneration in PD depending on microglial activation and at least partly TNF-α release.

Neuro-Immune Mechanisms Regulating Social Behavior: Dopamine as Mediator?

Social interactions are fundamental to survival and overall health. The mechanisms underlying social behavior are complex, but we now know that immune signaling plays a fundamental role in the regulation of social interactions. Prolonged or exaggerated alterations in social behavior often accompany altered immune signaling and function in pathological states. Thus, unraveling the link between social behavior and immune signaling is a fundamental challenge, not only to advance our understanding of human health and development, but for the design of comprehensive therapeutic approaches for neural disorders. In this review, we synthesize literature demonstrating the bidirectional relationship between social behavior and immune signaling and highlight recent work linking social behavior, immune function, and dopaminergic signaling in adolescent neural and behavioral development.

ADHD pathogenesis in the immune, endocrine and nervous systems of juvenile and maturating SHR and WKY rats.

RATIONALE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioural disorders with morphological and functional brain abnormalities. However, there is a growing body of evidence that abnormalities in the immune and endocrine systems may also account for the ADHD pathogenesis. OBJECTIVES: To test ADHD pathogenesis in neurological, immune and endocrine systems, this study examined the concentrations of cytokines, chemokines, oxidative stress markers, metabolic parameters, steroid hormones and steroidogenic enzymes in the serum and/or tissues of spontaneously hypertensive rats (SHRs, animal model of ADHD) and Wistar Kyoto rats (WKYs, control animals). Moreover, the volume of the medial prefrontal cortex (mPFC) as well as the density of dopamine 2 (D2) receptor-expressing cells and tyrosine hydroxylase (TH)-positive nerve fibres in it was also elucidated. METHODS: Peripheral blood, spleen and adrenal gland samples, as well as brain sections collected on day 35 (juvenile) and day 70 (maturating) from SHRs and WKYs, were processed by ELISA and immunohistochemistry, respectively. RESULTS: The results show significant increases of serum and/or tissue concentrations of cytokines, chemokines and oxidative stress markers in juvenile SHRs when compared to the age-matched WKYs. These increases were accompanied by a lowered volume of the mPFC and up-regulation of D2 in this brain region. In maturating SHRs, the levels of inflammatory and oxidative stress markers were normalised and accompanied by elevated contents of steroid hormones. CONCLUSIONS: Significant elevations of serum and/or tissue contents of cytokines, chemokines and oxidative stress markers as well as volumetric and neurochemical alterations in the mPFC of juvenile SHRs may suggest the cooperation of neurological and immune systems in the ADHD pathogenesis. Elevated levels of steroid hormones in maturating SHRs may be a compensatory effect involved in reducing inflammation and ADHD symptoms.

Dopamine and its receptors play a role in the modulation of CCR5 expression in innate immune cells following exposure to Methamphetamine: Implications to HIV infection.

The Human Immunodeficiency Virus (HIV) infects cells in the Central Nervous System (CNS), where the access of antiretrovirals and antibodies that can kill the virus may be challenging. As a result of the early HIV entry in the brain, infected individuals develop inflammation and neurological deficits at various levels, which are aggravated by drugs of abuse. In the non-human primate model of HIV, we have previously shown that drugs of abuse such as Methamphetamine (Meth) increase brain viral load in correlation with a higher number of CCR5-expressing myeloid cells. CCR5 is a chemokine receptor that may be involved in increasing inflammation, but also, it is a co-receptor for viral entry into target cells. CCR5-expressing myeloid cells are the main targets of HIV in the CNS. Thus, the identification of factors and mechanisms that impact the expression of CCR5 in the brain is critical, as changes in CCR5 levels may affect the infection in the brain. Using a well-characterized in vitro system, with the THP1 human macrophage cell line, we have investigated the hypothesis that the expression of CCR5 is acutely affected by Meth, and examined pathways by which this effect could happen. We found that Meth plays a direct role by regulating the abundance and nuclear translocation of transcription factors with binding sites in the CCR5 promoter. However, we found that the main factor that modifies the CCR5 gene promoter at the epigenetic level towards transcription is Dopamine (DA), a neurotransmitter that is produced primarily in brain regions that are rich in dopaminergic neurons. In THP1 cells, the effect of DA on innate immune CCR5 transcription was mediated by DA receptors (DRDs), mainly DRD4. We also identified a role for DRD1 in suppressing CCR5 expression in this myeloid cell system, with potential implications for therapy. The effect of DA on innate immune CCR5 expression was also detectable on the cell surface during acute time-points, using low doses. In addition, HIV Tat acted by enhancing the surface expression of CCR5, in spite of its poor effect on transcription. Overall, our data suggests that the exposure of myeloid cells to Meth in the context of presence of HIV peptides such as Tat, may affect the number of HIV targets by modulating CCR5 expression, through a combination of DA-dependent and-independent mechanisms. Other drugs that increase DA may affect similar mechanisms. The implications of these epigenetic and translational mechanisms in enhancing HIV infection in the brain and elsewhere are demonstrated.

Dopaminergic Stimulation of Myeloid Antigen-Presenting Cells Attenuates Signal Transducer and Activator of Transcription 3-Activation Favouring the Development of Experimental Autoimmune Encephalomyelitis.

The dual potential to promote tolerance or inflammation to self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. Previous results have shown that stimulation of dopamine receptor D5 (DRD5) in DCs potentiates their inflammatory behaviour, favouring the development of experimental autoimmune encephalomyelitis (EAE). Here, we aimed to decipher the underlying mechanism and to test its relevance in multiple sclerosis (MS) patients. Our data shows that DRD5-deficiency confined to DCs in EAE mice resulted in reduced frequencies of CD4+ T-cell subsets with inflammatory potential in the central nervous system, including not only Th1 and Th17 cells but also granulocyte-macrophage colony-stimulating factor producers. Importantly, ex vivo depletion of dopamine from DCs resulted in a dramatic reduction of EAE severity, highlighting the relevance of an autocrine loop promoting inflammation in vivo. Mechanistic analyses indicated that DRD5-signalling in both mouse DCs and human monocytes involves the attenuation of signal transducer and activator of transcription 3-activation, a transcription factor that limits the production of the inflammatory cytokines interleukin (IL)-12 and IL-23. Furthermore, we found an exacerbated expression of all dopamine receptors in peripheral blood pro-inflammatory monocytes obtained from MS patients. These findings illustrate a novel mechanism by which myeloid antigen-presenting cells may trigger the onset of their inflammatory behaviour promoting the development of autoimmunity.

The implication of neuronimmunoendocrine (NIE) modulatory network in the pathophysiologic process of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder implicitly marked by the substantia nigra dopaminergic neuron degeneration and explicitly characterized by the motor and non-motor symptom complexes. Apart from the nigrostriatal dopamine depletion, the immune and endocrine study findings are also frequently reported, which, in fact, have helped to broaden the symptom spectrum and better explain the pathogenesis and progression of PD. Nevertheless, based on the neural, immune, and endocrine findings presented above, it is still difficult to fully recapitulate the pathophysiologic process of PD. Therefore, here, in this review, we have proposed the neuroimmunoendocrine (NIE) modulatory network in PD, aiming to achieve a more comprehensive interpretation of the pathogenesis and progression of this disease. As a matter of fact, in addition to the classical motor symptoms, NIE modulatory network can also underlie the non-motor symptoms such as gastrointestinal, neuropsychiatric, circadian rhythm, and sleep disorders in PD. Moreover, the dopamine (DA)-melatonin imbalance in the retino-diencephalic/mesencephalic-pineal axis also provides an alternative explanation for the motor complications in the process of DA replacement therapy. In conclusion, the NIE network can be expected to deepen our understanding and facilitate the multi-dimensional management and therapy of PD in future clinical practice.