An integrated cytokine and kynurenine network as the basis of neuroimmune communication.

Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of 'tonic' kynurenine pathway affecting baseline activity and the superimposed 'phasic' cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.

An Investigation into Proteomic Constituents of Cerebrospinal Fluid in Patients with Chronic Peripheral Neuropathic Pain Medicated with Opioids- a Pilot Study.

The pharmacodynamics of opioids for chronic peripheral neuropathic pain are complex and likely extend beyond classical opioid receptor theory. Preclinical evidence of opioid modulation of central immune signalling has not been identified in vivo in humans. Examining the cerebrospinal fluid (CSF) of patients medicated with opioids is required to identify potential pharmacodynamic mechanisms. We compared CSF samples of chronic peripheral neuropathic pain patients receiving opioids (n = 7) versus chronic peripheral neuropathic pain patients not taking opioids (control group, n = 13). Baseline pain scores with demographics were recorded. Proteome analysis was performed using mass spectrometry and secreted neuropeptides were measured by enzyme-linked immunosorbent assay. Based on Gene Ontology analysis, proteins involved in the positive regulation of nervous system development and myeloid leukocyte activation were increased in patients taking opioids versus the control group. The largest decrease in protein expression in patients taking opioids were related to neutrophil mediated immunity. In addition, notably higher expression levels of neural proteins (85%) and receptors (80%) were detected in the opioid group compared to the control group. This study suggests modulation of CNS homeostasis, possibly attributable to opioids, thus highlighting potential mechanisms for the pharmacodynamics of opioids. We also provide new insights into the immunomodulatory functions of opioids in vivo.

An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline.

Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells(PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry. The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001). The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05). Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-ß (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.

Celiac Vagus Nerve Stimulation Recapitulates Angiotensin II-Induced Splenic Noradrenergic Activation, Driving Egress of CD8 Effector Cells.

Angiotensin II (AngII) is a peptide hormone that affects the cardiovascular system, not only through typical effects on the vasculature, kidneys, and heart, but also through less understood roles mediated by the brain and the immune system. Here, we address the hard-wired neural connections within the autonomic nervous system that modulate splenic immunity. Chronic AngII infusion triggers burst firing of the vagus nerve celiac efferent, an effect correlated with noradrenergic activation in the spleen and T cell egress. Bioelectronic stimulation of the celiac vagus nerve, in the absence of other challenges and independently from afferent signals to the brain, evokes the noradrenergic splenic pathway to promote release of a growth factor mediating neuroimmune crosstalk, placental growth factor (PlGF), and egress of CD8 effector T cells. Our findings also indicate that the neuroimmune interface mediated by PlGF and necessary for transducing the neural signal into an effective immune response is dependent on α-adrenergic receptor signaling.

Reverse Signaling of Tumor Necrosis Factor Superfamily Proteins in Macrophages and Microglia: Superfamily Portrait in the Neuroimmune Interface.

The tumor necrosis factor (TNF) superfamily (TNFSF) is a protein superfamily of type II transmembrane proteins commonly containing the TNF homology domain. The superfamily contains more than 20 protein members, which can be released from the cell membrane by proteolytic cleavage. Members of the TNFSF function as cytokines and regulate diverse biological processes, including immune responses, proliferation, differentiation, apoptosis, and embryogenesis, by binding to TNFSF receptors. Many TNFSF proteins are also known to be responsible for the regulation of innate immunity and inflammation. Both receptor-mediated forward signaling and ligand-mediated reverse signaling play important roles in these processes. In this review, we discuss the functional expression and roles of various reverse signaling molecules and pathways of TNFSF members in macrophages and microglia in the central nervous system (CNS). A thorough understanding of the roles of TNFSF ligands and receptors in the activation of macrophages and microglia may improve the treatment of inflammatory diseases in the brain and periphery. In particular, TNFSF reverse signaling in microglia can be exploited to gain further insights into the functions of the neuroimmune interface in physiological and pathological processes in the CNS.

Pain in spondyloarthritis: A neuro-immune interaction.

Pain in spondyloarthritis is usually attributed to inflammation. However, treatment with potent biologic agents that control inflammation does not always control the pain. Pain is hence likely to be multifactorial. Fatigue is another prominent feature of this condition which again tends to respond poorly to potent biologic agents. There is also a growing interest in coexisting fibromyalgia in this group of patients and how this affects response to biologic therapies. Advances in neuroimaging have helped in better understanding the dynamic nature of brain networks in the perception of pain. Animal models have helped in developing concepts of peripheral and central sensitization in pain transmission. This review discusses the neuroimmune basis of pain in ankylosing spondylitis, with an emphasis on brain networks and the complex interactions between the nervous system and the immune system at various levels. It also provides some insights into the differences in pain perception between men and women.

Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression.

Bidirectional communication links operate between the brain and the body. Afferent immune-to-brain signals are capable of inducing changes in mood and behavior. Chronic heavy alcohol drinking, typical of alcohol use disorder (AUD), is one such factor that provokes an immune response in the periphery that, by means of circulatory cytokines and other neuroimmune mediators, ultimately causes alterations in the brain function. Alcohol can also directly impact the immune functions of microglia, the resident immune cells of the central nervous system (CNS). Several lines of research have established the contribution of specific inflammatory mediators in the development and progression of depressive illness. Much of the available evidence in this field stems from cross-sectional data on the immune interactions between isolated AUD and major depression (MD). Given their heterogeneity as disease entities with overlapping symptoms and shared neuroimmune correlates, it is no surprise that systemic and CNS inflammation could be a critical determinant of the frequent comorbidity between AUD and MD. This review presents a summary and analysis of the extant literature on neuroimmune interface in the AUD-MD comorbidity.