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.

Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence.

Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers. ILC3 development is thought to be programmed, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial­ILC3­epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals.

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.

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.

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.

Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis.

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENT Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.

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.

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.

Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis.

Substance P (SP) is an undecapeptide present in the CNS and the peripheral nervous system. SP released from the peripheral nerves exerts its biological and immunological activity via high-affinity neurokinin 1 receptor (NK1R). SP is also produced by immune cells and acts as an autocrine or paracrine fashion to regulate the function of immune cells. In addition to its proinflammatory role, SP and its metabolites in combination with insulin-like growth factor-1 are shown to promote the corneal epithelial wound healing. Recently, we showed an altered ocular surface homeostasis in unmanipulated NK1R-/- mice, suggesting the role of SP-NK1R signaling in ocular surface homeostasis under steady-state. This review summarizes the immunobiology of SP and its effect on immune cells and immunity to microbial infection. In addition, the effect of SP in inflammation, wound healing, and corneal epithelial homeostasis in the eye is discussed.

Neurotransmitter signalling via NMDA receptors leads to decreased T helper type 1-like and enhanced T helper type 2-like immune balance in humans.

Given the pivotal roles that CD4+ T cell imbalance plays in human immune disorders, much interest centres on better understanding influences that regulate human helper T-cell subset dominance in vivo. Here, using primary CD4+ T cells and short-term T helper type 1 (Th1) and Th2-like lines, we investigated roles and mechanisms by which neurotransmitter receptors may influence human type 1 versus type 2 immunity. We hypothesized that N-methyl-d-aspartate receptors (NMDA-R), which play key roles in memory and learning, can also regulate human CD4+ T cell function through induction of excitotoxicity. Fresh primary CD4+ T cells from healthy donors express functional NMDA-R that are strongly up-regulated upon T cell receptor (TCR) mediated activation. Synthetic and physiological NMDA-R agonists elicited Ca2+ flux and led to marked inhibition of type 1 but not type 2 or interleukin-10 cytokine responses. Among CD4+ lines, NMDA and quinolinic acid preferentially reduced cytokine production, Ca2+ flux, proliferation and survival of Th1-like cells through increased induction of cell death whereas Th2-like cells were largely spared. Collectively, the findings demonstrate that (i) NMDA-R is rapidly up-regulated upon CD4+ T cell activation in humans and (ii) Th1 versus Th2 cell functions such as proliferation, cytokine production and cell survival are differentially affected by NMDA-R agonists. Differential cytokine production and proliferative capacity of Th1 versus Th2 cells is attributable in part to increased physiological cell death among fully committed Th1 versus Th2 cells, leading to increased Th2-like dominance. Hence, excitotoxicity, beyond its roles in neuronal plasticity, may contribute to ongoing modulation of human T cell responses.

Getting nervous about immunity.

Twenty-five years ago, immunologists and neuroscientists had little science of mutual interest. This is no longer the case. Neuroscientists now know that the first formally defined cytokine, IL-1, activates a discrete population of hypothalamic neurons. This interaction leads to the release of glucocorticoids from the adrenal gland, a hormone that has a long history in immunoregulation. Immunologists have been surprised to learn that lymphoid cells synthesize acetylcholine, the first formally recognized neurotransmitter. This neurotransmitter suppresses the synthesis of TNF. These discoveries blur the distinction of neuroscience and immunology as distinct disciplines. There are now 37 formally recognized cytokines and their receptors, and at least 60 classical neurotransmitters plus over 50 neuroactive peptides. These findings explain why both immunologists and neuroscientists are getting nervous about immunity and highlight a real need to apply integrative physiological approaches in biomedical research.

Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.

The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5'-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the apo form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the holo → apo conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5'-phosphate-binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies.

Autonomic regulation of the immune system in cardiovascular diseases.

The autonomic nervous system is a powerful regulator of circulatory adjustments to acute hemodynamic stresses. Here we focus on new concepts that emphasize the chronic influence of the sympathetic and parasympathetic systems on cardiovascular pathology. The autonomic neurohumoral system can dramatically influence morbidity and mortality from cardiovascular disease through newly discovered influences on the innate and adaptive immune systems. Specifically, the end-organ damage in heart failure or hypertension may be worsened or alleviated by pro- or anti-inflammatory pathways of the immune system, respectively, that are activated through neurohumoral transmitters. These concepts provide a major new perspective on potentially life-saving therapeutic interventions in the deadliest of diseases.

[Changes of the innervation in the mucous membrane and glands of the tongue in early and late experimental diabetes mellitus]. / A nyelv nyálkahártya és mirigyek innervációjának változása korai és késoi kisérletes diabetes mellitusban.

The number of the different neuropeptides-containing nerve fibres and immunocompetent cells was changed in diabetes mellitus (DM) in different organs. In this work we investigated the effect of DM on quantitation of the nerve fibres using immunhistochemistry. After two weeks of the DM the quantitiy of the different nerve fibres increased significantly both in the mucous membrane and glands of the tongue. The number of the immunocompetent cells (lymphocytes, plasma cells, mast cells) increased as well significantly. Some of these cells showed also immunoreactivity for substance P and neuropeptide Y. A few substance P cells were in very close relation to the SP immunoreactive nerve fibres. After four weeks of DM the number of the nerve fibres was decreased compared to the 2 weeks treatment, however, the number of them was higher compared to the control. The close correlation between the nerve fibres and immune cells might play a crucial role in maintaining the homeostasis in the mucous membrane and glands of the tongue as well as in the increasing inflammation and elimination of it.

Neuropeptide signaling activates dendritic cell-mediated type 1 immune responses through neurokinin-2 receptor.

Neurokinin A (NKA), a neurotransmitter distributed in the central and peripheral nervous system, strictly controls vital responses, such as airway contraction, by intracellular signaling through neurokinin-2 receptor (NK2R). However, the function of NKA-NK2R signaling on involvement in immune responses is less-well defined. We demonstrate that NK2R-mediated neuropeptide signaling activates dendritic cell (DC)-mediated type 1 immune responses. IFN-γ stimulation significantly induced NK2R mRNA and remarkably enhanced surface protein expression levels of bone marrow-derived DCs. In addition, the DC-mediated NKA production level was significantly elevated after IFN-γ stimulation in vivo and in vitro. We found that NKA treatment induced type 1 IFN mRNA expressions in DCs. Transduction of NK2R into DCs augmented the expression level of surface MHC class II and promoted Ag-specific IL-2 production by CD4(+) T cells after NKA stimulation. Furthermore, blockade of NK2R by an antagonist significantly suppressed IFN-γ production by both CD4(+) T and CD8(+) T cells stimulated with the Ag-loaded DCs. Finally, we confirmed that stimulation with IFN-γ or TLR3 ligand (polyinosinic-polycytidylic acid) significantly induced both NK2R mRNA and surface protein expression of human PBMC-derived DCs, as well as enhanced human TAC1 mRNA, which encodes NKA and Substance P. Thus, these findings indicate that NK2R-dependent neuropeptide signaling regulates Ag-specific T cell responses via activation of DC function, suggesting that the NKA-NK2R cascade would be a promising target in chronic inflammation caused by excessive type 1-dominant immunity.

Ratio of antibodies to neurotransmitters in the serum of students, occasional drug users.

The survey included volunteer students of secondary and higher educational institutions. Two groups have been formed based on the results of clinical and laboratory studies. Group 1 comprised students occasionally using cannabinoids and amphetamines (risk group for psychoactive substances addiction) and group 2 included students who do not use drugs. The serum level of autoantibodies to norepinephrine, dopamine, and serotonin was reduced in the risk group.

[Antibodies to neurotransmitters as possible neuroimmune risk markers of formation dependence to psychoactive substances].

In the sera of patients with opioid addiction has been found elevated levels of autoantibodies to the neurotransmitters dopamine, norepinephrine and serotonin in comparison with a control group of healthy people of the same age. In the group of patients with acute withdrawal was showed a reduction of antibody to dopamine, noradrenaline and serotonin in the blood serum when compared with patients in the period of postabstinent disorders. In the group of patients with risk for the formation of substance dependence in serum was observed decrease in autoantibodies to dopamine and norepinephrine compared with the control group.

[The role of antibodies to neurotransmitters of antinociceptive system in mechanisms of neuropathic pain].

The present investigation was undertaken in order to study the role of the antibodies to neurotransmitters of antinociceptive system in pathogenesis of neuropathic pain on models of neuropathic pain. It was shown that the development of experimental neuropathic pain syndrome is accompanied with induction of autoantibodies to CABA, serotonin, noradrenalin and dopamine. It was established that the antibodies to neurotransmitters of antinociceptive system have a pronociceptive effect.