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  • CT Neuroendocrine immune papers

    http://journal.frontiersin.org/artic...014.00143/full

    Neuro-endocrine networks controlling immune system in health and disease

    The nervous and immune systems have long been considered as compartments that perform separate and different functions. However, recent clinical, epidemiological, and experimental data have suggested that the pathogenesis of several immune-mediated disorders, such as multiple sclerosis (MS), might involve factors, hormones, and neural mediators that link the immune and nervous system. These molecules are members of the same superfamily, which allow the mutual and bi-directional neural–immune interaction. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones that control food intake and metabolism, has suggested that nutritional/metabolic status, acting at central level, can control immune self-tolerance, since it promotes experimental autoimmune encephalomyelitis, an animal model of MS. Here, we summarize the most recent advances and the key players linking the central nervous system, immune tolerance, and the metabolic status. Understanding this coordinated interaction may pave the way for novel therapeutic approaches to increase host defense and suppress immune-mediated disorders.
    Immune-Surveillance in the Control of CNS
    In physiological conditions, the immune system monitors the integrity of the brain and spinal cord (immune-surveillance), in order to highlight any inflammatory mediators resulting from infection and damage. In this context, a key role in the control of immune-surveillance is played by the resident microglia and immune cells (16). Indeed microglial cells are able to activate the adaptive immune system, when required, and these glia cells are in turn modulated by endogenous mechanisms, thus confirming the tune control of immune system in the CNS (17). Microglia secrete neurotrophins, such as nerve growth factor (NGF), able to sustain neuronal and macroglial survival and growth. In addition to microglia, peripheral immune cells can reach the inflammatory site in the CNS, through mechanisms similar to those observed in peripheral organs. T cells travel into the CNS through transient interactions with CNS endothelium, which expresses cell adhesion molecules, moreover other immune cells (macrophages and dendritic cells) are located at the interface between the blood and brain, where they can promote antigen presentation and a powerful inflammatory response (18). Non-activated microglia express low levels of HLA-DR in the healthy human brain and MHC-II molecules (MHC-II, CD80, CD86, CD40, CD11a) in the rodent brain, thus suggesting their antigen presentation capability (19–24).

    Recent evidence has revealed that T cells can be found in the CSF of healthy individuals, indicating that these cells can reach the CNS through the choroid plexus and meninges (25, 26). They have been characterized as CD4+CD45RA−CD27+CD69+ activated central memory T cells (27, 28), which expressed high levels of CCR7, CXCR3, and L-selectin (29, 30) and are located in brain areas, which lack of tight junctions in the BBB (31).
    The Autonomic Nervous System
    The control of inflammation is realized by two major mechanisms: self-controlling immune mechanisms and brain-derived immunoregulatory output. The CNS regulates immune function, inflammation, and pathogens responses against host tissues, through the production of inhibitory cytokines, hormones, and other soluble molecules able to signal to the brain, which in turn exerts strong regulatory effects on the immune response (5, 32). Brain immunoregulatory action is mediated by the autonomic nervous system, through sympathetic and vagus nerve innervation. Recent evidence has reported that afferent neurons express receptors for several pro-inflammatory cytokines, such as tumor necrosis factor (TNF), IL-1, activating neural reflex circuits that regulates acute and chronic immune responses (5). A prototypical example of neural circuit is the inflammatory reflex mediated by the vagus nerve and the α7 subunit of the nicotinic acetylcholine receptor (α7 nAChR) expressed on immune cells (33).

    Vagus nerve activation determines NE release from splenic neurons, which through the binding to β2 adrenergic receptor expressed on splenic T cells, favors choline acetyltransferase stimulation with consequent acetylcholine production (34) (Figure 1). T cell receptor (TCR)-mediated stimulation of splenic T cells significantly enhances their ability to produce acetylcholine, which binds to α7 nAChR expressed on macrophages resident in the red pulp and marginal zone of the spleen (35), thus suppressing NF-κB activity and consequently reducing cytokine synthesis (33, 35) (Figure 1). Activation of this pathway by electrical stimulation of the vagus nerve or administration of α7 selective agonists improves inflammation and survival in different clinical conditions (34).
    All these data have been confirmed also in humans; indeed patients with autoimmune disease and non-resolving inflammation display impaired vagus nerve signaling, which favors the progression of inflammation (32), whereas vagus nerve stimulation is able to attenuate leukocytes migration into the joints of synovitis affected patients (36). In line with this evidence, α7 nAChR deficient mice have increased synovial inflammation when compared to their littermate controls in a model of collagen-induced arthritis (37, 38). Treatment with α7 nAChR agonists or electrical vagus nerve stimulation significantly decreases arthritis in wild-type (WT) mice with collagen-induced arthritis. Finally, diet can also influence the inflammatory reflex; indeed dietary consumption of fish oil, significantly enhances the vagus nerve stimulation, favoring resolution of inflammation (39). On the other hand, in condition of obesity, where there is an inappropriate energy deposit and expenditure, leading to low grade inflammation and metabolic disease, an impaired vagus nerve activity has been found (40).
    The Peptidergic Pathway: Neuropeptides
    Recent evidence suggests a key role of the neuropeptidergic pathway in the control of immune system (54, 55). Activation of nociceptors leads to local axon reflexes through the release of neuropeptides [i.e., calcitonin gene-related peptide (CGRP), substance P (SP), adrenomedullin, neurokinins A and B, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and gastrin releasing peptide (GRP), etc.], which locally recruit and activate both innate and adaptive immune cells. More specifically, it has been shown that these mediators sustain chemotaxis and activation of neutrophils, macrophages, lymphocytes, and mast cells, increase the presenting capability of antigen presenting cells (APCs) and stimulate signaling to vascular endothelial cells, enhancing the recruitment of inflammatory leukocytes (55, 56) (Figure 1).

    Another possible way of communication between immune cells and nociceptor neurons is also mediated by cytokine release. Indeed, sensory neurons display several cytokine receptors such as IL-1β receptor (IL-1βR) and TNF-α receptor (TNF-αR), which are able to recognize factors secreted by immune cells (i.e., IL-1β, TNF-α, NGF). They also express danger-associated molecular pattern (DAMP) receptors, toll-like receptors (TLRs), pathogen-associated molecular patterns (PAMPs), which recognize exogenous environmental signals (i.e., heat, acidity, chemicals, bacteria, viruses) or endogenous danger signals (i.e., ATP concentration, uric acid, hydroxynonenals) (56, 57), enhancing T cell functions (proliferation, cytokine secretion, and adhesion molecules expression) and thus representing a relevant player in CNS–immune system crosstalk in normal and pathophysiological conditions (58–61). In activated macrophages, VIP inhibits the expression of pro-inflammatory cytokines and chemokines (62–64), sustaining the differentiation of CD4+ T cells in Th2 cells and promoting their proliferation and/or survival (64, 65). Among the other neuropeptides, several functions of the cellular immune system have been shown to be regulated by NPY, SP, and related-agouti protein (AgRP) (66). NPY is a neuropeptide that increases food intake and storage of energy as fat but it is also able to modulate lymphocytes proliferation, NK activity, and interleukin-2 (IL-2) and TNF-α release (67). SP stimulates lymphocyte migration, proliferation, and IgA secretion and promotes phagocytosis and chemotaxis in innate immune cells, during inflammation (68). On the other hand, AgRP is co-expressed with NPY and works by increasing appetite and decreasing metabolism and energy expenditure. Hypothalamic AgRP neurons are mandatory for feeding and survival (69, 70) and they mediate effects of the histone deacetylase, Sirt1, on energy metabolism (71, 72). Recently, it has been shown that these neurons are involved in the regulation of adaptive immune responses. Indeed, knockdown of Sirt1 in Agrp neurons induce a pro-inflammatory state, characterized by a decrease in regulatory T cell functions with consequent increase of effector T cell activity, which determines an increased autoimmune disease susceptibility (73). This finding together with a recent paper by Luquet’s group (74) confirms the notion that the sympathetic nervous system may play a central role in mediating the effect of impaired function of AgRP neurons on immune system activity.
    Cytokines-Related Pathway
    It is becoming well accepted that products of the immune system (cytokines) can signal the brain that infection has occurred. This cytokine-to-brain communication can result in marked alterations in brain function and behavior. In general, cytokines may traffic to the CNS at sites where the BBB is absent (75, 76), by carrier-mediated transport mechanisms, or by generating central mediators altering the permeability of the BBB to other substances (5, 77). Cytokines may also act directly on the CNS, by stimulating peripheral afferent neurons (5, 78). Indeed, peripherally generated cytokines can stimulate vagus nerve, which represents another very important pathway through which signals reach the brain (79). Several cytokines such as IL-1, IL-2, IL-6, IFN-γ, and TNF-α can regulate the activation of the HPA axis and are also influenced by glucocorticoid secretion (52, 80). IL-1 is one of the most studied cytokines linking immunological activation with the brain functions (81–83). Indeed, IL-1 has been shown to influence hypothalamic neurosecretory activity by stimulating CRH release by hypothalamic CRH neurons, and to enhance the turnover of NE in the hypothalamus (84, 85). IL-1 is also produced by several type of cells resident in the CNS, including astrocytes and microglia (86, 87) and IL-1 receptors have been identified in different brain areas, such as hippocampus and the dorsal raphe nucleus (88, 89). Furthermore, mRNA for IL-1α and TNF-α has been demonstrated in anterior pituitary cells (90, 91), which secrete IL-6 as well (91). IL-1 has been shown to be pivotal for the recruitment of leukocytes across the BBB. Indeed, recent studies have demonstrated that intracerebroventricular injection of IL-1β as well as IFN-γ and TNF-α induce neutrophils and leukocytes infiltration into the brain tissue (92), in a mouse model of experimental autoimmune encephalomyelitis (EAE) (93), by increasing the production of P-selectin on brain endothelial cells (94). In addition, also receptors for IL-2 were found in specific brain areas such as the hippocampal formation (95, 96) and it has been recently shown that that IL-2 deficiency results in altered septal and hippocampal structure, associated with changes in neurotrophins production (97).
    Leptin: At the Crossroad between CNS and Immune System Function
    Leptin, the product of the obese (ob) gene, has been recently recognized as one of the most studied molecule linking CNS, nutrition, metabolism, and immune homeostasis (98). Leptin is mainly produced by the adipose tissue in proportion to the body fat mass and also by tissues such as the stomach, skeletal muscle, and placenta (98). At central level, this hormone regulates food intake, bone mass homeostasis, autonomic nervous system outflow, and the secretion of HPA hormones (98). Originally, leptin has been identified as the hormone responsible for the regulation of the balance between food intake and energy expenditure, being able to signal to the brain any changes in stored energy. However recent evidence has indicated that leptin is much more than a “fat-o-stat” sensor (99–101); indeed, leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mice are not only strongly obese, but they also display several alterations, due to the effects of leptin on reproduction (102), hematopoiesis (103), angiogenesis (104), metabolism of bone (105), lipids and glucose (98) and, more importantly, innate and adaptive immunity (106, 107).
    It is becoming increasingly evident that there is a dense and intricate relationship between the immune and nervous system (146). This type of interaction is explicated through the production of molecules (cytokines, hormones, and peptides) from the CNS and through the activation of afferent and efferent neurological pathways in lymphoid organs, with both immuno-suppressive and immuno-stimulating effects. On the other hand, also the cytokines themselves are able to communicate with the CNS and ensure the passage of specific signals and information from the periphery to the brain. In this context, leptin represents a key factor linking immune system, metabolism, and CNS functions.



    Immune Signals in the Brain

    http://jonlieffmd.com/blog/immune-si...f038d-90589721

    Update 15/05/2017



    The therapeutic potential of targeting chemokine signalling in the treatment of chronic pain

    http://onlinelibrary.wiley.com/doi/1...46b3972d4b14e1

    Abstract

    Chronic pain is a distressing condition, which is experienced even when the painful stimulus, whether surgery or disease related, has subsided. Current treatments for chronic pain show limited efficacy and come with a host of undesirable side-effects, and thus there is a need for new, more effective therapies to be developed. The mechanisms underlying chronic pain are not fully understood at present, although pre-clinical models have facilitated the progress of this understanding considerably in the last decade. The mechanisms underlying chronic pain were initially thought to be neurocentric. However, we now appreciate that non-neuronal cells play a significant role in nociceptive signalling through their communication with neurons. One of the major signalling pathways, which mediates neuron/non-neuronal communication, is chemokine signalling. In this review, we discuss selected chemokines that have been reported to play a pivotal role in the mechanisms underlying chronic pain in a variety of pre-clinical models. Approaches that target each of the chemokines discussed in this review come with their advantages and disadvantages; however, the inhibition of chemokine actions is emerging as an innovative therapeutic strategy, which is now reaching the clinic, with the chemokine Fractalkine and its CX3CR1 receptor leading the way.

    This article is part of the special article series “Pain”.
    Update 17/05/2017
    Last edited by Jo Bowyer; 17-05-2017, 06:15 PM.
    Jo Bowyer
    Chartered Physiotherapist Registered Osteopath.
    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

  • #2
    Massage-like stroking boosts the immune system in mice

    http://www.nature.com/srep/2015/1506...srep10913.html

    Abstract
    Recent clinical evidence suggests that the therapeutic effect of massage involves the immune system and that this can be exploited as an adjunct therapy together with standard drug-based approaches. In this study, we investigated the mechanisms behind these effects exploring the immunomodulatory function of stroking as a surrogate of massage-like therapy in mice. C57/BL6 mice were stroked daily for 8 days either with a soft brush or directly with a gloved hand and then analysed for differences in their immune repertoire compared to control non-stroked mice. Our results show that hand- but not brush-stroked mice demonstrated a significant increase in thymic and splenic T cell number (p < 0.05; p < 0.01). These effects were not associated with significant changes in CD4/CD8 lineage commitment or activation profile. The boosting effects on T cell repertoire of massage-like therapy were associated with a decreased noradrenergic innervation of lymphoid organs and counteracted the immunosuppressive effect of hydrocortisone in vivo. Together our results in mice support the hypothesis that massage-like therapies might be of therapeutic value in the treatment of immunodeficiencies and related disorders and suggest a reduction of the inhibitory noradrenergic tone in lymphoid organs as one of the possible explanations for their immunomodulatory function.
    The main aim of this study was to investigate the effect of massage-like stroking on the immune system in an experimental model. Both human (finger-driven) and non-human (brush stroke-driven) stroking showed a trend towards an increase in T cell number in lymphoid organs. However, only hand-delivered-stroking showed a statistical significant difference compared to control, reinforcing the hypothesis that the application of a controlled pressure might not be the sole parameter that contributes to the therapeutic effect of massage17. Other factors like the warmth or consistency of the contact area (the fingers in our case) might play a role.
    Aiming to better understand the possible mechanism behind the observed differences in T cellularity, we first sought to investigate if this boosting action of massage on T cells was somehow linked to the hedonistic value of stroking and massaging on mood as it is often described for humans17. Our results suggested that this was not associated with significant difference in the levels of anxiety-like behaviour. There are many possible explanations for this discrepancy such as the length of the treatment itself not being enough to be “translated” into significant changes in anxiety-like behaviour (8 days as opposed to weeks) or, most likely, the absence of a modulatory effect of our massage-like paradigm on anxiety. In this regard it is interesting to note that studies addressing the handling of mice with tunnels have reported similar findings e.g. that handling does not always have an anxiolytic effect as this seems to be dependent on the strain of the mice, the experimental test used and, last but not least, the social interaction with other mice39, 40.

    These surprising results contradict our initial hypothesis that the positive emotional response elicited by the massage would be ultimately linked to its immunomodulatory effect and prompted us to explore other possible mechanisms. Previous studies performed in humans have suggested that massage could either enhance vagal activity via stimulation of pressure receptors that ultimately signal the limbic system41, 42 or decrease the release of norepinephrine in the blood stream causing an overall down regulation of sympathetic activity43, 44. Intriguingly, studies by our own lab and other research groups have shown sympathetic nerves that innervate lymphoid tissues as one of the major pathways by which the neuronal and immune system communicate to maintain body homeostasis35, 45, 46, 47, 48. Most importantly, evidence suggests that this homeostatic cross-talk is responsible for the “processing of information” such as behavioural conditioning or changes of external environmental factors and its translation into specific immune responses32, 49.

    Our analysis of the noradrenergic tone present in the thymus and spleen of stroked mice supported these findings and showed a drastic reduction in nerve density and noradrenaline content when compared to control mice. Thymic noradrenergic nerves originate primarily from the superior cervical and stellate ganglia and enter the thymus with large blood vessels, ending into the capsule and interlobular septa. From these vascular nerve plexuses, smaller vascular plexuses diverge into the cortex. The spleen instead receives a rich supply of sympathetic nerves primarily from the superior mesenteric and celiac ganglionic plexuses and its noradrenergic innervation is distributed extensively to various parts of the spleen including capsule, trabeculae, red pulp, and white pulp47, 50, 51. The functional significance of this intricate network is to provide both potentiation and inhibition of immune functions. In our studies, the decreased noradrenergic tone of both thymus and spleen caused a significant increase in T cell cellularity as it has been observed in other settings through pharmacological or surgical reduction of the noradrenergic tone35. This boost in T cell number was not accompanied by changes in TCR response in vitro, as shown by our tests on mature T cell activation, supporting the idea that the immunomodulatory effects we observed in vivo might be due to the lymphoid organ microenvironment, rather than a direct effect at the level of T lymphocyte gene expression e.g. to their capacity to expand and proliferate.

    How does massage-like stroking decrease noradrenergic tone? Although we have not fully addressed this question, there is growing evidence in the literature supporting the concept of an interactive network between cutaneous nerves, the neuroendocrine axis and the immune system. Based on these theories, the skin can be genuinely considered a neuroimmunoendocrine organ that controls a wide variety of functions through the peripheral sensory nervous system, the autonomous nervous system, as well as the central nervous system (for an in depth review on the topic see52). This idea has been further substantiated by a recent novel study by Vrontou et al.22, that has identified unmyelinated C type sensory neurons that detect massage-like stroking on hairy skin in mice. These neurons, named MRGPRB4+, exclusively innervate hairy skin and have been shown to be closely related to the C-LTMRs found in humans22. Most strikingly, these fibres terminate in the substantia dorsal horn of the spinal cord with neurons53 that give projections to the insular cortex54, an area of the brain concerned with wellbeing and emotion55, but also shown to play a crucial role in the central autonomic network90. Sympathetic nerve responses to insular cortical stimulation are mediated by synapses within the lateral hypothalamic area and ventrolateral medulla91, the brain structures linked with immunomodulation92.

    Notwithstanding the importance of fully investigating the cellular and molecular mechanisms behind the immunomodulatory function of massage, one of the major findings of this study is the confirmation in experimental animals of observations made in humans for the effectiveness of massage in the treatment of immunodeficiencies3, 56, 57, 58. The concept that massage has ‘recovering’ properties is well known in the field of sport medicine where it has been shown that massage has an important immunoregulatory function after strenuous exercise59, 60. More specifically, massage has been shown to favour recovery from the transient immunosuppressive state induced by exercise through release of more cells in the circulation and controlling the infiltration of inflammatory cells into the muscles61, 62. Similarly, there are some evidences that massage may support the recovery of immune function during periods of immunosuppression, counteracting the loss of T cells in patients suffering from cancer and HIV infection3, 16, 19, 58. Although peripherally comparable to these studies, our results support these findings and suggest that massage contribute to the maintenance of immunocompetence.
    My italics
    Jo Bowyer
    Chartered Physiotherapist Registered Osteopath.
    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

    Comment


    • #3
      Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

      http://physrev.physiology.org/content/86/4/1309

      Abstract

      This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.
      Jo Bowyer
      Chartered Physiotherapist Registered Osteopath.
      "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

      Comment


      • #4
        Fetal Programming of the Neuroendocrine-Immune System and Metabolic Disease

        http://www.hindawi.com/journals/jp/2012/792934/

        Abstract

        Adverse uterine environments experienced during fetal development can alter the projected growth pattern of various organs and systems of the body, leaving the offspring at an increased risk of metabolic disease. The thrifty phenotype hypothesis has been demonstrated as an alteration to the growth trajectory to improve the survival and reproductive fitness of the individual. However, when the intrauterine environment does not match the extrauterine environment problems can arise. With the increase in metabolic diseases in both Westernized and developing countries, it is becoming apparent that there is an environmental disconnect with the extrauterine environment. Therefore, the focus of this paper will be to explore the effects of maternal malnutrition on the offspring’s susceptibility to metabolic disorders such as obesity, cardiovascular disease, and diabetes with emphasis on programming of the neuroendocrine-immune system.
        1. Introduction

        Early life events such as those experienced in utero have the ability to shape the phenotype of an individual in an effort to prepare the fetus for extrauterine life. This is typically referred to as developmental or fetal programming and suggests that adverse uterine environments can “permanently” alter the metabolic, endocrine, and immune function parameters of individuals well into adulthood. There appear to be critical windows during development in which the fetus is most sensitive to environmental cues, altering the projected plan of growth. For instance, maternal adversity experienced during gestation will convey signals to the fetus that the environment in which it is to live is less than optimal, altering the developmental programming of the various organs and systems in the body to better match life outside the uterus. As various tissues and systems in the body mature and differentiate at different rates during fetal development, there appear to be critical periods in development when they are most sensitive to this adversity. The hypothalamic-pituitary-adrenal axis (HPAA), for example, undergoes much growth and differentiation during early and late gestation in species such as humans, primates, and sheep, and these are the periods when it is most sensitive to developmental programming alterations [1–3]. Alterations in metabolic function such as glucose tolerance and insulin sensitivity are greatly affected during mid- and late gestation as metabolic parameters are undergoing much differentiation during this period [4].

        The alterations in developmental programming trajectories are assumed to provide an adaptive advantage for the individual to its new environment, referred to as the “thrifty phenotype”. A reduction in birth weight has been one alteration observed following adverse changes in the uterine environment. It is postulated that this alteration in growth pattern allowed the fetus to reallocate the available energy to more vital processes such as organ function [5]. The Leningrad wartime famine cohort of 1941 to 1944 is a classic example of the thrifty phenotype, demonstrating that maternal malnutrition during gestation primed the fetus by repartitioning metabolic energy for life in a malnourished society, ensuring survival and reproductive fitness [6]. However, when the developmental programming does not match the environment in which the individuals are to live, problems can arise.
        Jo Bowyer
        Chartered Physiotherapist Registered Osteopath.
        "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

        Comment


        • #5
          Enlargement of choroid plexus in complex regional pain syndrome

          http://www.nature.com/articles/srep14329

          Abstract
          The choroid plexus, located in brain ventricles, has received surprisingly little attention in clinical neuroscience. In morphometric brain analysis, we serendipitously found a 21% increase in choroid plexus volume in 12 patients suffering from complex regional pain syndrome (CRPS) compared with age- and gender-matched healthy subjects. No enlargement was observed in a group of 8 patients suffering from chronic pain of other etiologies. Our findings suggest involvement of the choroid plexus in the pathogenesis of CRPS. Since the choroid plexus can mediate interaction between peripheral and brain inflammation, our findings pinpoint the choroid plexus as an important target for future research of central pain mechanisms.
          The choroid plexus is the key producer of cerebrospinal fluid, which provides a fluid cushion for the central nervous system and a sink for nervous-system biomarkers and debris1,2. The choroid plexus also secretes into the cerebrospinal fluid a wide array of proteins and other signaling substances that instruct the development and maintenance of the mammalian brain2. Moreover, the choroid plexus provides a point of entry for immune cells into the brain, thereby linking the peripheral and central inflammatory systems3,4.
          Jo Bowyer
          Chartered Physiotherapist Registered Osteopath.
          "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

          Comment


          • #6
            Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder

            http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179746/

            Abstract
            Major depressive disorder (MDD) poses one of the highest disease burdens worldwide. Yet, current treatments targeting serotonergic and noradrenaline reuptake systems are insufficient to provide long-term relief from depressive symptoms in most patients, indicating the need for new treatment targets. Having the ability to influence behavior similar to depressive symptoms, as well as communicate with neuronal and neuroendocrine systems, the innate immune system is a strong candidate for MDD treatments. Given the complex nature of immune signaling, the main question becomes: What is the role of the innate immune system in MDD? The current review presents evidence that toll-like receptor 4 (TLR4), via driving both peripheral and central immune responses, can interact with serotonergic neurotransmission and cause neuroendocrine disturbances, thus integrating with widely observed hallmarks of MDD. Additionally, through describing the multi-directional communication between immune, neural and endocrine systems in stress, TLR4—related mechanisms can mediate stress-induced adaptations, which are necessary for the development of MDD. Therefore, apart from exogenous pathogenic mechanisms, TLR4 is involved in immune changes as a result of endogenous stress signals, playing an integral part in the pathophysiology, and could be a potential target for pharmacological treatments to improve current interventions for MDD.
            Keywords: toll-like receptor 4, TLR4, HPA, neuroendocrine, neuroimmunology, stress, depression, MDD
            Jo Bowyer
            Chartered Physiotherapist Registered Osteopath.
            "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

            Comment


            • #7
              Structural and Functional Brain Remodeling during Pregnancy with Diffusion Tensor MRI and Resting-State Functional MRI

              http://journals.plos.org/plosone/art...l.pone.0144328

              Mammalian females, from rodents to primates, undergo fundamental behavioral changes during pregnancy [1, 2]. Before pregnancy, female mammals are largely self-directed species that satisfy their own needs for survival. During pregnancy, they become focused on the care and well-being of their future offspring [1, 2]. Previous studies have reported that pregnancy-induced behavioral changes are associated with the hippocampal functions. For example, improvements in learning and memory and enhancement in object recognition and placement during pregnancy are related to functions of dorsal hippocampus whereas reduction in stress responsiveness and anxiety is related to functions of the ventral hippocampus [1, 3–6]. These pregnancy-induced behavioral changes may be associated with reproductive hormonal changes [7]. Estrogen and progesterone are produced in the ovaries and placenta during pregnancy, whereas prolactin and oxytocin are secreted by the hypothalamus and pituitary gland. These hormonal changes have been previously shown to remodel the brain at the neuronal level [1]. For example, estrogen and progesterone can increase dendritic spine density and neuronal excitability in the hippocampus, particularly the dentate gyrus [1, 8–11]. Prolactin can enhance white matter regeneration in the brain, and may mediate neurogenesis in the forebrain [12–14]. Oxytocin increases the firing of inhibitory hippocampal neurons, and may enhance hippocampal spike transmission [15, 16].
              Jo Bowyer
              Chartered Physiotherapist Registered Osteopath.
              "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

              Comment


              • #8
                Surfing DNA: Enzyme catches a ride to fight infection

                http://www.sciencedaily.com/releases...1218090218.htm

                Scientists have shown for the first time that an enzyme crucial to keeping our immune system healthy "surfs" along the strands of DNA inside our cells.

                The researchers used extremely powerful microscopy to watch how the enzyme AID (activation-induced deoxycytidine deaminase) moves around and interacts with other molecules.

                They were able to see that it catches a free ride on top of another enzyme, which has its own motor. "Before now, no one has shown that an enzyme can ride on top of a motor-enzyme," says David Rueda who leads the Single Molecule Imaging group at the MRC Clinical Sciences Centre at Imperial College, and who led the team whose research is published in Nature Communications.

                AID helps our immune system to recognise and respond to pathogens such as bacteria and viruses. Each strain of pathogen has a unique pattern of molecules on its surface. These molecules come in all shapes and sizes, so that the immune system can distinguish between different pathogens.
                Jo Bowyer
                Chartered Physiotherapist Registered Osteopath.
                "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                Comment


                • #9
                  Novel mechanism that helps activated dendritic cells to initiate effective immunity

                  http://www.cell.com/immunity/abstrac...showall%3Dtrue

                  Highlights
                  •TLR4 engagement of DCs for 16 hr increases cross-presentation in vivo and in vitro
                  •Phagosomes of maturing DCs recruit less lysosomal enzymes becoming less degradative
                  •LPS-treated DCs display clustering of lysosomes and reduced phago-lysosomal fusion
                  •Rab34 controls lysosome organization thus increasing cross-presentation efficiency

                  Summary
                  The initiation of cytotoxic immune responses by dendritic cells (DCs) requires the presentation of antigenic peptides derived from phagocytosed microbes and infected or dead cells to CD8+ T cells, a process called cross-presentation. Antigen cross-presentation by non-activated DCs, however, is not sufficient for the effective induction of immune responses. Additionally, DCs need to be activated through innate receptors, like Toll-like receptors (TLRs). During DC maturation, cross-presentation efficiency is first upregulated and then turned off. Here we show that during this transient phase of enhanced cross-presentation, phago-lysosome fusion was blocked by the topological re-organization of lysosomes into perinuclear clusters. LPS-induced lysosomal clustering, inhibition of phago-lysosome fusion and enhanced cross-presentation, all required expression of the GTPase Rab34. We conclude that TLR4 engagement induces a Rab34-dependent re-organization of lysosomal distribution that delays antigen degradation to transiently enhance cross-presentation, thereby optimizing the priming of CD8+ T cell responses against pathogens.
                  Keywords:
                  antigen presentation, cross-presentation, dendritic cell, GTPase Rab34, phagocytosis, phagosome maturation, Toll-like receptor 4





                  Activity-dependent trafficking of lysosomes in dendrites and dendritic spines


                  http://jcb.rupress.org/content/216/8/2499 Abstract


                  I
                  n neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins.
                  protein-turnover-neurosciencneews.jpg?w=750.jpg



                  Lysosomes were identified in dendrites and dendritic spines using various techniques. Cultured neurons show lysosomes throughout neurons and in dendritic spines indicated in yellow (left and upper right); brain slices show a lysosome in the head of the spine highlighted in green (middle right); and transmission electron microscopy reveals a lysosome (black circle) near the base of a spine (bottom right). NeuroscienceNews.com image is credited to Marisa Goo, Gentry Patrick/UC San Diego.
                  Last edited by Jo Bowyer; 07-08-2017, 10:47 PM.
                  Jo Bowyer
                  Chartered Physiotherapist Registered Osteopath.
                  "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                  Comment


                  • #10
                    Aerobic fitness in late adolescence and the risk of early death: a prospective cohort study of 1.3 million Swedish men

                    http://ije.oxfordjournals.org/conten.../20/ije.dyv321

                    Abstract

                    Background: Fitness level and obesity have been associated with death in older populations. We investigated the relationship between aerobic fitness in late adolescence and early death, and whether a high fitness level can compensate the risk of being obese.

                    Methods: The cohort comprised 1 317 713 Swedish men (mean age, 18 years) that conscripted between 1969 and 1996. Aerobic fitness was assessed by an electrically braked cycle test. All-cause and specific causes of death were tracked using national registers. Multivariable adjusted associations were tested using Cox regression models.

                    Results: During a mean follow-up period of 29 years, 44 301 subjects died. Individuals in the highest fifth of aerobic fitness were at lower risk of death from any cause [hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.47–0.51] in comparison with individuals in the lowest fifth, with the strongest association seen for death related to alcohol and narcotics abuse (HR, 0.20; 95% CI, 0.15–0.26). Similar risks were found for weight-adjusted aerobic fitness. Aerobic fitness was associated with a reduced risk of death from any cause in normal-weight and overweight individuals, whereas the benefits were reduced in obese individuals (P < 0.001 for interaction). Furthermore, unfit normal-weight individuals had 30% lower risk of death from any cause (HR, 0.70; 95% CI, 0.53–0.92) than did fit obese individuals.

                    Conclusions: Low aerobic fitness in late adolescence is associated with an increased risk of early death. Furthermore, the risk of early death was higher in fit obese individuals than in unfit normal-weight individuals.
                    Jo Bowyer
                    Chartered Physiotherapist Registered Osteopath.
                    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                    Comment


                    • #11
                      Misaligned feeding impairs memories

                      http://elifesciences.org/content/4/e09460

                      Abstract

                      Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is challenged by inappropriate meal- or work-times. Here we scheduled food access to the sleep time and examined the impact on learning and memory in mice. Under these conditions, we demonstrate that the molecular clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the molecular clock in the hippocampus is synchronized by the timing of food availability. This chronic circadian misalignment causes reduced hippocampal long term potentiation and total CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in hippocampal-dependent learning and memory. Our findings suggest that the timing of meals have far-reaching effects on hippocampal physiology and learned behaviour.
                      Introduction

                      The circadian system is a finely tuned network of central and peripheral oscillators headed by a master pacemaker, the suprachiasmatic nucleus (SCN), which governs daily rhythms in physiology and behaviour, including cognition. This network regulates cognitive processes (Holloway and Wansley, 1973; Chaudhury and Colwell, 2002), and the neural circuits involved in learning and memory also exhibit circadian rhythms in gene expression and synaptic plasticity (Eckel-Mahan et al., 2008; Fropf et al., 2014; Lamont et al., 2005; Lyons, 2006). Genetic disruption of these molecular oscillations has severe consequences on cognition (Van der Zee et al., 2008; Wang et al., 2009; Wardlaw et al., 2014). Environmental perturbations also have the capacity to disrupt synchrony and misalign this clock network (Fekete et al., 1985; Cho et al., 2000; Devan et al., 2001; Ruby et al., 2008; Loh et al., 2010; Gibson et al., 2010; Karatsoreos et al., 2011; Fonken et al., 2012; LeGates et al., 2012; Fernandez et al., 2014) and are problematic as many people in our modern society extend their work and recreation into the night hours.

                      There has been mounting evidence that the timing of when we eat is critical for our metabolic health (Bass, 2012; Mattson et al., 2014). At this point, timing of food intake is well-established to have a major impact on the phase of the molecular oscillations in peripheral organs such as the liver and pancreas (Damiola, 2000; Stokkan, 2001). Mis-timed meals during the sleep phase accelerates weight gain compared with animals fed during their wake phase (Arble et al., 2009; Bray et al., 2013), whereas wake-phase feeding has a protective effect against the cardiac and metabolic dysfunction caused by high fat diets (Hatori et al., 2012; Gill et al., 2015). Similar disruptive effects are seen in humans, where misaligned mealtimes produce cardiac and metabolic deficits, leading to a pre-diabetic state (Scheer et al., 2009). We thus became interested in the possibility that these ill consequences of eating at inappropriate phases of the daily cycle may also be maladaptive for cognitive function. In this study, we sought to determine the effects of chronic but stable misalignment of the circadian network by scheduling access to food at an inappropriate phase of the daily cycle. We demonstrate that this simple manipulation has far-reaching consequences for learning and memory.
                      Jo Bowyer
                      Chartered Physiotherapist Registered Osteopath.
                      "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                      Comment


                      • #12
                        Dopamine and the Creative Mind: Individual Differences in Creativity Are Predicted by Interactions between Dopamine Genes DAT and COMT

                        http://journals.plos.org/plosone/art...l.pone.0146768

                        Abstract

                        The dopaminergic (DA) system may be involved in creativity, however results of past studies are mixed. We attempted to clarify this putative relation by considering the mediofrontal and the nigrostriatal DA pathways, uniquely and in combination, and their contribution to two different measures of creativity–an abbreviated version of the Torrance Test of Creative Thinking, assessing divergent thinking, and a real-world creative achievement index. We found that creativity can be predicted from interactions between genetic polymorphisms related to frontal (COMT) and striatal (DAT) DA pathways. Importantly, the Torrance test and the real-world creative achievement index related to different genetic patterns, suggesting that these two measures tap into different aspects of creativity, and depend on distinct, but interacting, DA sub-systems. Specifically, we report that successful performance on the Torrance test is linked with dopaminergic polymorphisms associated with good cognitive flexibility and medium top-down control, or with weak cognitive flexibility and strong top-down control. The latter is particularly true for the originality factor of divergent thinking. High real-world creative achievement, on the other hand, as assessed by the Creative Achievement Questionnaire, is linked with dopaminergic polymorphisms associated with weak cognitive flexibility and weak top-down control. Taken altogether, our findings support the idea that human creativity relies on dopamine, and on the interaction between frontal and striatal dopaminergic pathways in particular. This interaction may help clarify some apparent inconsistencies in the prior literature, especially if the genes and/or creativity measures were analyzed separately.
                        Jo Bowyer
                        Chartered Physiotherapist Registered Osteopath.
                        "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                        Comment


                        • #13
                          Inducible chromatin priming is associated with the establishment of immunological memory in T cells

                          http://emboj.embopress.org/content/e...embj.201592534

                          Abstract

                          Immunological memory is a defining feature of vertebrate physiology, allowing rapid responses to repeat infections. However, the molecular mechanisms required for its establishment and maintenance remain poorly understood. Here, we demonstrated that the first steps in the acquisition of T‐cell memory occurred during the initial activation phase of naïve T cells by an antigenic stimulus. This event initiated extensive chromatin remodeling that reprogrammed immune response genes toward a stably maintained primed state, prior to terminal differentiation. Activation induced the transcription factors NFAT and AP‐1 which created thousands of new DNase I‐hypersensitive sites (DHSs), enabling ETS‐1 and RUNX1 recruitment to previously inaccessible sites. Significantly, these DHSs remained stable long after activation ceased, were preserved following replication, and were maintained in memory‐phenotype cells. We show that primed DHSs maintain regions of active chromatin in the vicinity of inducible genes and enhancers that regulate immune responses. We suggest that this priming mechanism may contribute to immunological memory in T cells by facilitating the induction of nearby inducible regulatory elements in previously activated T cells.
                          Jo Bowyer
                          Chartered Physiotherapist Registered Osteopath.
                          "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                          Comment


                          • #14
                            Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages

                            http://www.cell.com/cell/abstract/S0...showall%3Dtrue
                            Highlights
                            •Gut lamina propria and muscularis macrophages show unique intra-tissue adaptation
                            •Muscularis macrophages express a tissue-protective gene profile
                            •Gut extrinsic sympathetic innervation is activated upon distal bacterial infection
                            •β2 adrenergic receptor signaling mediates MM polarization upon bacterial infection

                            Summary
                            Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.

                            my italics
                            Last edited by Jo Bowyer; 23-01-2016, 11:39 AM.
                            Jo Bowyer
                            Chartered Physiotherapist Registered Osteopath.
                            "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                            Comment


                            • #15
                              New findings point to central nervous system role in painful diabetic peripheral nerve disease

                              http://www.sciencedaily.com/releases...0127121602.htm

                              Studies using advanced imaging techniques are providing new insights into the role of the CNS (brain and spinal cord) in the development of diabetic peripheral neuropathy (DPN) as well as its symptoms. According to a report by Dr. Solomon Tesfaye of Sheffield (UK) Teaching Hospitals NHS Foundation Trust and colleagues, "Although DPN has been considered a disease of the peripheral nerve, from numerous studies it is becoming apparent that there are indeed changes within the CNS that...appear to be concomitant with the evolution of painful and painless DPN."

                              Diabetic Peripheral Neuropathy--Not Just 'Peripheral'?

                              Diabetic peripheral neuropathy occurs in about one-half of all patients with diabetes. About half of these--that is, one-fourth of all people with diabetes--have pain and other symptoms of DNP. In addition to progressive and severe pain, patients with DNP have insensitivity to trauma, placing them at risk of foot ulcerations, infections, and amputations.

                              Several general risk factors for DPN have been identified, including poor control of blood glucose levels, high cholesterol, and obesity. But there is little information on factors leading to the development of painful DPN.

                              Previous studies have focused on the peripheral mechanisms of DPN--including "dying back" of nerve cells (from the furthest point upward) and loss of the myelin "insulation" of nerve cells. There is now strong evidence that small blood vessel disease leading to reduced oxygen supply (hypoxia) to the peripheral nerves contributes to the development of DPN. But there are still no "consistently unique" tests or indicators associated with painful DPN.

                              Researchers are now looking beyond the peripheral nerves to CNS factors that might explain the development of painful DNP. Those studies--using sophisticated MRI and magnetic resonance spectroscopy techniques--have led to a number of findings suggesting a role of the CNS, including:

                              Differences in the cross-sectional area (width) of the spinal cord, particularly before symptoms of DPN have appeared.

                              Loss of volume (atrophy) in the primary sensory cortex--the main brain area involved in sense of touch.

                              Differences in blood supply in a part of the brain called the thalamus--oversupply (hyperperfusion) in painful DPN, compared with undersupply (hypoperfusion) in painless DPN.

                              Changes in higher brain areas, specifically the "pain processing matrix"--thought to be involved not only in detecting the location and intensity of pain but also the emotional (affective) responses.

                              Reductions in the brain gray matter, particularly in areas where "somatosensory perceptions" are processed.
                              Jo Bowyer
                              Chartered Physiotherapist Registered Osteopath.
                              "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

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