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.

Antidepressants on Multiple Sclerosis: A Review of In Vitro and In Vivo Models.

Background: Increased prevalence of depression has been observed among patients with multiple sclerosis (MS) and correlated with the elevated levels of proinflammatory cytokines and the overall deregulation of monoaminergic neurotransmitters that these patients exhibit. Antidepressants have proved effective not only in treating depression comorbid to MS, but also in alleviating numerous MS symptoms and even minimizing stress-related relapses. Therefore, these agents could prospectively prove beneficial as a complementary MS therapy. Objective: This review aims at illustrating the underlying mechanisms involved in the beneficial clinical effects of antidepressants observed in MS patients. Methods: Through a literature search we screened and comparatively assessed papers on the effects of antidepressant use both in vitro and in vivo MS models, taking into account a number of inclusion and exclusion criteria. Results: In vitro studies indicated that antidepressants promote neural and glial cell viability and differentiation, reduce proinflammatory cytokines and exert neuroprotective activity by eliminating axonal loss. In vivo studies confirmed that antidepressants delayed disease onset and alleviated symptoms in Experimental Autoimmune Encephalomyelitis (EAE), the most prevalent animal model of MS. Further, antidepressant agents suppressed inflammation and restrained demyelination by decreasing immune cell infiltration of the CNS. Conclusion: Antidepressants were efficient in tackling numerous aspects of disease pathophysiology both in vitro and in vivo models. Given that several antidepressants have already proved effective in clinical trials on MS patients, the inclusion of such agents in the therapeutic arsenal of MS should be seriously considered, following an individualized approach to minimize the adverse events of antidepressants in MS patients.

T Cells Plead for Rejuvenation and Amplification; With the Brain's Neurotransmitters and Neuropeptides We Can Make It Happen.

T cells are essential for eradicating microorganisms and cancer and for tissue repair, have a pro-cognitive role in the brain, and limit Central Nervous System (CNS) inflammation and damage upon injury and infection. However, in aging, chronic infections, acute SARS-CoV-2 infection, cancer, chronic stress, depression and major injury/trauma, T cells are often scarce, exhausted, senescent, impaired/biased and dysfunctional. People with impaired/dysfunctional T cells are at high risk of infections, cancer, other diseases, and eventually mortality, and become multi-level burden on other people, organizations and societies. It is suggested that "Nerve-Driven Immunity" and "Personalized Adoptive Neuro-Immunotherapy" may overcome this problem. Natural Neurotransmitters and Neuropeptides: Glutamate, Dopamine, GnRH-II, CGRP, Neuropeptide Y, Somatostatin and others, bind their well-characterized receptors expressed on the cell surface of naïve/resting T cells and induce multiple direct, beneficial, and therapeutically relevant effects. These Neurotransmitters and Neuropeptides can induce/increase: gene expression, cytokine secretion, integrin-mediated adhesion, chemotactic migration, extravasation, proliferation, and killing of cancer. Moreover, we recently found that some of these Neurotransmitters and Neuropeptides also induce rapid and profound decrease of PD-1 in human T cells. By inducing these beneficial effects in naïve/resting T cells at different times after binding their receptors (i.e. NOT by single effect/mechanism/pathway), these Neurotransmitters and Neuropeptides by themselves can activate, rejuvenate, and improve T cells. "Personalized Adaptive Neuro-Immunotherapy" is a novel method for rejuvenating and improving T cells safely and potently by Neurotransmitters and Neuropeptides, consisting of personalized diagnostic and therapeutic protocols. The patient's scarce and/or dysfunctional T cells are activated ex vivo once by pre-selected Neurotransmitters and/or Neuropeptides, tested, and re-inoculated to the patient's body. Neuro-Immunotherapy can be actionable and repeated whenever needed, and allows other treatments. This adoptive Neuro-Immunotherapy calls for testing its safety and efficacy in clinical trials.

[Orexin A as mediator in the gut-brain dialogue]. / Orexina A como mediadora en el diálogo intestino-cerebro.

INTRODUCTION: The orexinergic system is one of the chemical mediators that modulate the gut-brain axis, given the involvement of hypothalamic orexin A (OXA) in gastrointestinal motility and secretion, and the presence of OXA in enteroendocrine cells of the intestinal mucosa and in primary afferent neurons of the mesenteric plexus, permitting its participation in gut-brain signaling. AIM: The source of OXA and the signal(s) triggering its peripheral release are not fully understood, and it is not known whether it acts on orexigenic receptors in peripheral tissues to meet physiological or pathological demands. The aim of this review is to address these questions in the light of new data indicating that OXA may have functions in the gut-brain axis that go beyond its participation in energy homeostasis. DEVELOPMENT: OXA in the enteric system protects against systemic and central inflammation, and hypothalamic OXA orchestrates numerous peripheral effects to suppress the systemic inflammatory response. For this reason, OXA may act as an immunomodulator in chronic inflammations or autoimmune diseases. OXA is also involved in the stress response, regulating physiological responses to emotional or stressful stimuli. CONCLUSIONS: OXA exerts anti-inflammatory and gastroprotective effects on the intestinal mucosa; however, it may increase the response to external and/or internal stress in individuals with chronic inflammation, exacerbating the gastrointestinal inflammation. Hence, pharmacologic interventions in the orexinergic system have been proposed to treat diseases in which intestinal hypersensitivity is combined with appetite loss, sleep disturbance, stress, and anxiety.

TITLE: Orexina A como mediadora en el diálogo intestino-cerebro.Introducción. Entre los mediadores químicos que modulan el eje intestino-cerebro debe incluirse el sistema orexinérgico, ya que la orexina A (OXA) hipotalámica interviene en la motilidad y en la secreción gastrointestinal. También está presente en las células enteroendocrinas de la mucosa intestinal y en las neuronas aferentes primarias del plexo mientérico, y puede intervenir en la señalización intestino-cerebro. Objetivo. No se conoce con exactitud la fuente ni la señal que originan la liberación de OXA periférica, ni tampoco si actúa en los receptores orexinérgicos de los tejidos periféricos ante demandas fisiológicas o patológicas. Esta revisión intenta analizar estas cuestiones a la luz de nuevos datos que indican que la OXA en el eje intestino-cerebro puede tener funciones más allá de su participación en la homeostasis energética. Desarrollo. La OXA en el sistema entérico protege de la inflamación sistémica y central, y en el hipotálamo orquesta numerosos efectos periféricos para suprimir la respuesta inflamatoria sistémica. Por ello, podría actuar como sustancia inmunomoduladora en inflamaciones crónicas o en enfermedades autoinmunitarias. La OXA también se relaciona con la respuesta de estrés, regulando las respuestas fisiológicas a estímulos emocionales o estresantes. Conclusiones. Aunque la OXA tiene efectos antiinflamatorios y gastroprotectores de la mucosa intestinal, en procesos de inflamación crónica podría incrementar la respuesta a estímulos estresantes, tanto externos como internos, y exacerbar la inflamación gastrointestinal. Por ello, se han propuesto intervenciones farmacológicas sobre el sistema orexinérgico como tratamiento para enfermedades en las que la hipersensibilidad intestinal coexiste con pérdida de apetito, alteraciones del sueño, estrés y ansiedad.

A Gut Feeling: The Importance of the Intestinal Microbiota in Psychiatric Disorders.

The intestinal microbiota constitutes a complex ecosystem in constant reciprocal interactions with the immune, neuroendocrine, and neural systems of the host. Recent molecular technological advances allow for the exploration of this living organ and better facilitates our understanding of the biological importance of intestinal microbes in health and disease. Clinical and experimental studies demonstrate that intestinal microbes may be intimately involved in the progression of diseases of the central nervous system (CNS), including those of affective and psychiatric nature. Gut microbes regulate neuroinflammatory processes, play a role in balancing the concentrations of neurotransmitters and could provide beneficial effects against neurodegeneration. In this review, we explore some of these reciprocal interactions between gut microbes and the CNS during experimental disease and suggest that therapeutic approaches impacting the gut-brain axis may represent the next avenue for the treatment of psychiatric disorders.

Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review.

The existence of the neural control of mast cell functions has long been proposed. Mast cells (MCs) are localized in association with the peripheral nervous system (PNS) and the brain, where they are closely aligned, anatomically and functionally, with neurons and neuronal processes throughout the body. They express receptors for and are regulated by various neurotransmitters, neuropeptides, and other neuromodulators. Consequently, modulation provided by these neurotransmitters and neuromodulators allows neural control of MC functions and involvement in the pathogenesis of mast cell-related disease states. Recently, the roles of individual neurotransmitters and neuropeptides in regulating mast cell actions have been investigated extensively. This review offers a systematic review of recent advances in our understanding of the contributions of neurotransmitters and neuropeptides to mast cell activation and the pathological implications of this regulation on mast cell-related disease states, though the full extent to which such control influences health and disease is still unclear, and a complete understanding of the mechanisms underlying the control is lacking. Future validation of animal and in vitro models also is needed, which incorporates the integration of microenvironment-specific influences and the complex, multifaceted cross-talk between mast cells and various neural signals. Moreover, new biological agents directed against neurotransmitter receptors on mast cells that can be used for therapeutic intervention need to be more specific, which will reduce their ability to support inflammatory responses and enhance their potential roles in protecting against mast cell-related pathogenesis.

Critical Neurotransmitters in the Neuroimmune Network.

Immune cells rely on cell-cell communication to specify and fine-tune their responses. They express an extensive network of cell communication modes, including a vast repertoire of cell surface and transmembrane receptors and ligands, membrane vesicles, junctions, ligand and voltage-gated ion channels, and transporters. During a crosstalk between the nervous system and the immune system these modes of cellular communication and the downstream signal transduction events are influenced by neurotransmitters present in the local tissue environments in an autocrine or paracrine fashion. Neurotransmitters thus influence innate and adaptive immune responses. In addition, immune cells send signals to the brain through cytokines, and are present in the brain to influence neural responses. Altered communication between the nervous and immune systems is emerging as a common feature in neurodegenerative and immunopathological diseases. Here, we present the mechanistic frameworks of immunostimulatory and immunosuppressive effects critical neurotransmitters - dopamine (3,4-dihydroxyphenethylamine), serotonin (5-hydroxytryptamine), substance P (trifluoroacetate salt powder), and L-glutamate - exert on lymphocytes and non-lymphoid immune cells. Furthermore, we discuss the possible roles neurotransmitter-driven neuroimmune networks play in the pathogenesis of neurodegenerative disorders, autoimmune diseases, cancer, and outline potential clinical implications of balancing neuroimmune crosstalk by therapeutic modulation.

Immunological Disturbances and Neuroimaging Findings in Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) Comorbid Patients.

Mood disorders and Major Depressive Disorder, in particular, appear to be some of the most common psychiatric disorders with a high rate of comorbidity most frequently of anxiety or substance abuse disorders (alcohol use disorder). In both cases - MDD and AUD, a number of immunological disturbances are observed, such as chronic mild inflammation response, increased level of cytokines, hypercortisolaemia, which lead to specific changes in brain neurotransmitter functions. Some of the contemporary brain imaging techniques are functional magnetic resonance imaging (fMRI) and magnetic spectroscopy which are most commonly used to assess the brain metabolism and functional connectivity changes such as altered responses to emotional stimuli in MDD or overactivation of ventromedial prefrontal areas during delayed and underactivation of dorsolateral prefrontal regions during impulsive reward decisions in AUD and dysfunction of gamma-aminobutyric acid (GABA) and/or glutamate neurotransmitter systems, low NAA and myo-Inositol in both MDD and AUD.

The role of neutrophils in neuro-immune modulation.

Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation between the nervous and immune systems. First, the role of neutrophils as a diffuse source of acetylcholine and catecholamines is controversial as well as the effects of these neurotransmitters in neutrophil's functions. Second, neutrophils contribute for the activation and sensitization of sensory neurons, and thereby, in events of nociception and pain. In addition, nociceptor activation promotes an axon reflex triggering a local release of neural mediators and provoking neutrophil activation. Third, the recruitment of neutrophils in inflammatory responses in the nervous system suggests these immune cells as innovative targets in the treatment of central infectious, neurological and neurodegenerative disorders. Multidisciplinary studies involving immunologists and neuroscientists are required to define the role of the neurons-neutrophils communication in the pathophysiology of infectious, inflammatory, and neurological disorders.

Neuronal regulation of group 2 innate lymphoid cells and type 2 inflammation.

Diverse infectious, inflammatory, and environmental stimuli induce type 2 inflammation in the body. Group 2 innate lymphoid cells (ILC2s) are potent producers of type 2 cytokines and play important roles in promoting type 2 inflammation. In addition to alarmins and other cytokines which are known to regulate ILC2 responses, emerging studies identified the regulation of ILC2s by the nervous system through neurotransmitter and neuropeptides. In this review, we highlight recent advances in the regulation of ILC2s and type 2 inflammation by the nervous system.

Major fundamental factors hindering immune system in defense against tumor cells: The link between insufficiency of innate immune responses, metabolism, and neurotransmitters with effector immune cells disability.

Despite the major progresses in comprehending the mechanisms of tumor immunosurveillance and the role of innate and adaptive immune systems in recent years, there are still a number of obstacles hindering successful and effective immunotherapy of cancer. Such obstacles have been mainly attributed to the ability of tumors in creating a tolerant microenvironment and exploiting a plethora of immunosuppressive factors that counter effective immune responses against tumor cells. Here we represent a new insight into probable links between immune system disability with metabolism and chronic psychological stress which is beyond the other strategies recruited by tumors to thwart tumor immunosurveillance. In addition, we underscore the prominent role of improper innate immune responses as one of the underlying causes of either pro-tumorigenic capability or tumor immunosurveillance failure. However the insufficiency of stimulatory factors in immune responses is a major fact leading to tumor survival, metabolic suppression of immune cells in tumor microenvironment, as well as the negative influences of chronic stress and depression in cancer patients are important parameters amplifying disability of immune responses which have mostly been underestimated in cancer immunotherapy. Stress-related catecholamines are suggested as immunosuppressive factors. In addition, tumor cells have distinct metabolic pathways and secrete various metabolites in the tumor microenvironment which may inhibit T cells activity. We believe that simultaneous control of metabolic and psychological negative influences on the tumor immunosurveillance, along with addressing the weak aspects of innate and adaptive immune responses in cancer immunotherapy may result in more successful treatment of tumors.

Autonomic regulation of T-lymphocytes: Implications in cardiovascular disease.

The nervous and immune systems both serve as essential assessors and regulators of physiological function. Recently, there has been a great interest in how the nervous and immune systems interact to modulate both physiological and pathological states. In particular, the autonomic nervous system has a direct line of communication with immune cells anatomically, and moreover, immune cells possess receptors for autonomic neurotransmitters. This circumstantial evidence is suggestive of a functional interplay between the two systems, and extensive research over the past few decades has demonstrated neurotransmitters such as the catecholamines (i.e. dopamine, norepinephrine, and epinephrine) and acetylcholine have potent immunomodulating properties. Furthermore, immune cells, particularly T-lymphocytes, have now been found to express the cellular machinery for both the synthesis and degradation of neurotransmitters, which suggests the ability for both autocrine and paracrine signaling from these cells independent of the nervous system. The details underlying the functional interplay of this complex network of neuroimmune communication are still unclear, but this crosstalk is suggestive of significant implications on the pathogenesis of a number of autonomic-dysregulated and inflammation-mediated diseases. In particular, it is widely accepted that numerous forms of cardiovascular diseases possess imbalanced autonomic tone as well as altered T-lymphocyte function, but a paucity of literature exists discussing the direct role of neurotransmitters in shaping the inflammatory microenvironment during the progression or therapeutic management of these diseases. This review seeks to provide a fundamental framework for this autonomic neuroimmune interaction within T-lymphocytes, as well as the implications this may have in cardiovascular diseases.

Neural stimulations regulate the infiltration of immune cells into the CNS.

The systemic regulation of immune reactions by the nervous system is well studied and depends on the release of hormones. Some regional regulations of immune reactions, on the other hand, depend on specific neural pathways. Better understanding of these regulations will expand therapeutic applications for neuroimmune and organ-to-organ functional interactions. Here, we discuss one regional neuroimmune interaction, the gateway reflex, which converts specific neural inputs into local inflammatory outputs in the CNS. Neurotransmitters released by the inputs stimulate specific blood vessels to express chemokines, which serve as a gateway for immune cells to extravasate into the target organ such as the brain or spinal cord. Several types of gateway reflexes have been reported, and each controls distinct CNS blood vessels to form gateways that elicit local inflammation, particularly in the presence of autoreactive immune cells. For example, neural stimulation by gravity creates the initial entry point to the CNS by CNS-reactive pathogenic CD4+ T cells at the dorsal vessels of fifth lumbar spinal cord, while pain opens the gateway at the ventral side of blood vessels in the spinal cord. In addition, it was recently found that local inflammation by the gateway reflex in the brain triggers the activation of otherwise resting neural circuits to dysregulate organ functions in the periphery including the upper gastrointestinal tract and heart. Therefore, the gateway reflex represents a novel bidirectional neuroimmune interaction that regulates organ functions and could be a promising target for bioelectric medicine.

The Influence of Antidepressants on the Immune System.

Depression is one of the most frequently diagnosed condition in psychiatry. Despite the availability of many preparations, over 30% of treated patients do not achieve remission. Recently the emphasis is put on the contribution of the body's inflammatory response as one of the causes of depression. The interactions between nervous and immune systems are the main issue addressed by psychoneuroimmunology. In patients suffering from depression changes in the plasma concentrations of cytokines and in the number and level of activation of immune cells has been found. Attention is paid to the high levels of pro-inflammatory cytokines, the prevalence of Th1 responses to Th2, weakening of NK cell cytotoxicity and changes in lymphocyte proliferation and apoptosis. A number of studies focus on influence of antidepressants and non-standard methods of depression treatment, such as ketamine infusion, on patients' immunology. Many of them seem to regulate the immune responses. The study results encourage to look for new ways to treat depression with immunomodulatory drugs. In this article authors present the current knowledge about immune system changes accompanying depression as well as the study results showing the influence of drugs on the immune system, especially in the context of reducing the symptoms of depression.

Glucocorticoids and sympathetic neurotransmitters modulate the acute immune response to Trypanosoma cruzi.

Evidence suggests that natural and adaptive immune responses can trigger neuroendocrine responses. Here, we discuss changes in the activity of the hypothalamus-pituitary-adrenal axis and in autonomic nerves, predominantly of the sympathetic nervous system, in a mouse model of acute infection with Trypanosoma cruzi. The endocrine response includes a marked increased release of glucocorticoid and a decrease of immune-stimulatory hormones, such as dehydroepiandrosterone sulfate, prolactin, and growth hormone during infection. These endocrine changes result in reduced proinflammatory cytokine production, increased regulatory/effector T cell ratio, and thymus atrophy. The sympathetic activity in the spleen of infected mice is also markedly reduced. However, the residual sympathetic activity can modulate the immune response to the parasite, as shown by increased mortality and production of proinflammatory cytokines in sympathetically denervated, infected mice. The outcome of the neuroendocrine response is the moderation of the intensity of the immune response to the parasite, an effect that results in delayed mortality in susceptible mice, and favors the course toward chronicity in more resistant animals.

Isoflurane anesthesia impairs the expression of immune neuromodulators in the hippocampus of aged mice.

Cognitive dysfunction is one of the most common postoperative complications experienced by older patients after anesthesia and surgery but the cause remains unknown. Immune molecules are essential for many aspects of neural homeostasis, including learning and memory, and an imbalance in immune neuromodulators is implicated in the development of neural dysfunction. Aging alters the control of neuroinflammatory cascades and general anesthetics are immunosuppressants. Therefore, we hypothesized that general anesthesia disturbs neuroimmune signaling in an age-dependent fashion. We tested this hypothesis by examining gene expression of key immune neuromodulators including IL-1ß, TNFα, and CCL2 in the hippocampus of young adult (3 mo) and aged (20 mo) mice following isoflurane anesthesia. We show that isoflurane anesthesia increases expression of these signaling molecules in the hippocampus of young adult mice but decreases it in the hippocampus of old mice. Furthermore, anesthetized old mice had an amplified hippocampal neuroimmune response to systemically administered lipopolysaccharide compared to age-matched carrier controls. Together, these data indicate that isoflurane anesthesia disrupts hippocampal neuroimmune mediator gene expression in the old brain and suggests a potential mechanism by which general anesthesia can contribute to disordered neuronal homeostasis and post-anesthesia cognitive disability in older subjects.

Neuroendocrine regulation of innate lymphoid cells.

The activities of the immune system in repairing tissue injury and combating pathogens were long thought to be independent of the nervous system. However, a major regulatory role of immunomodulatory molecules released locally or systemically by the neuroendocrine system has recently emerged. A number of observations and discoveries support indeed the notion of the nervous system as an immunoregulatory system involved in immune responses. Innate lymphoid cells (ILCs), including natural killer (NK) cells and tissue-resident ILCs, form a family of effector cells present in organs and mucosal barriers. ILCs are involved in the maintenance of tissue integrity and homeostasis. They can also secrete effector cytokines rapidly, and this ability enables them to play early roles in the immune response. ILCs are activated by multiple pathways including epithelial and myeloid cell-derived cytokines. Their functions are also regulated by mediators produced by the nervous system. In particular, the peripheral nervous system, through neurotransmitters and neuropeptides, works in parallel with the hypothalamic-pituitary-adrenal and gonadal axis to modulate inflammatory events and maintain homeostasis. We summarize here recent findings concerning the regulation of ILC activities by neuroendocrine mediators in homeostatic and inflammatory conditions.

Entamoeba histolytica L220 induces the in vitro activation of macrophages and neutrophils and is modulated by neurotransmitters.

The neuroimmunoregulation of inflammation has been well characterized. Entamoeba histolytica provokes an inflammatory response in the host in which macrophages and neutrophils are the first line of defense. The aim of this study was to analyze the effect of the 220 kDa lectin of Entamoeba histolytica on stimulation of human macrophages and neutrophils, especially the secretion of cytokines and the relation of these to neurotransmitters. Human cells were interacted with L220, epinephrine, nicotine, esmolol and vecuronium bromide. The concentrations of IL-1ß, IFN-γ, TNF-α and IL-10 were determined by ELISA at, 4 h of interaction. L220 has a cytokine stimulating function of macrophages and neutrophils for secretion of IL-1ß, and IL-10 only by macrophages, which was modulated by the effect of vecuronium on cholinergic receptors in this immune cells.