Stress and immunity: an integrated view of relationships between the brain and the immune system

The old notion that stress exacerbates the progression of physical illness via its corticosteroid-mediated immunosuppressive effects must be revised. Experimental and clinical studies demonstrate that both laboratory and natural stressors alter the activities of lymphocytes and macrophages in a complex way that depends on the type of immune response, the physical and psychological characteristics of the stressor and the timing of stress relative to the induction and expression of the immune event. The influences of stress on immunity are mediated not only by glucocorticoids but also by catecholamines, endogenous opioids and pituitary hormones such as growth hormone. Sensitivity of the immune system to stress is not simply fortuitous but is an indirect consequence of the regulatory reciprocal influences that exist between the immune system and the central nervous system. The immune system receives signals from the brain and the neuroendocrine system via the autonomic nervous system and hormones and sends information to the brain via cytokines. These connections appear to be part of a long-loop regulatory feedback system that plays an important role in the coordination of behavioral and physiological responses to infection and inflammation.     

Neural immune pathways and their connection to inflammatory diseases

Inflammation and inflammatory responses are modulated by a bidirectional communication between the neuroendocrine and immune system. Many lines of research have established the numerous routes by which the immune system and the central nervous system (CNS) communicate. The CNS signals the immune system through hormonal pathways, including the hypothalamic-pituitary-adrenal axis and the hormones of the neuroendocrine stress response, and through neuronal pathways, including the autonomic nervous system. The hypothalamic-pituitary-gonadal axis and sex hormones also have an important immunoregulatory role. The immune system signals the CNS through immune mediators and cytokines that can cross the blood-brain barrier, or signal indirectly through the vagus nerve or second messengers. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. This review discusses neuroimmune interactions and evidence for the role of such neural immune regulation of inflammation, rather than a discussion of the individual inflammatory mediators, in rheumatoid arthritis.     

The role of endogenous opioids and their receptors in the immune system.

Opioid peptides appear to be dynamic signaling molecules that are produced within the immune system and are active regulators of an immune response. Furthermore, the receptors for these peptides occurring on immunocyte membranes share characteristics with neuronal opioid receptors, including molecular size, immunogenicity, and the use of specific intracellular signaling pathways. Recent studies of the interaction of opioids with cytokines have indicated that opioid peptides are intimately involved within the immune system. Specifically, opioids, including 2-n-pentyloxy-2-phenyl-4-methyl-morpholine, naloxone, and beta-endorphin, have been shown to interact with IL-2 receptors (134) and regulate production of IL-1 and IL-2 (48-50, 135). Conversely, IL-1 has been shown to up-regulate opioid peptide binding in brain tissue (136). Furthermore, the induction of IL-1 by opioids has also been identified in the invertebrate Mytilus, indicating the evolutionary conservation of this relationship (137). These results seem to typify the intricate association between the immune and neuroendocrine systems through opioid pathways. It is predicted that future endeavors will use this relationship to diagnose and treat specific diseases that have at their basis neuroendocrine and immunologic imbalances.     

Ionotropic receptors in neuronal-astroglial signalling: What is the role of “excitable” molecules in non-excitable cells

Astroglial cells were long considered to serve merely as the structural and metabolic supporting cast and scenery against which the shining neurones perform their illustrious duties. Relatively recent evidence, however, indicates that astrocytes are intimately involved in many of the brain's functions. Astrocytes possess a diverse assortment of ionotropic transmitter receptors, which enable these glial cells to respond to many of the same signals that act on neurones. Ionotropic receptors mediate neurone-driven signals to astroglial cells in various brain areas including neocortex, hippocampus and cerebellum. Activation of ionotropic receptors trigger rapid signalling events in astroglia; these events, represented by local Ca²⁺ or Na⁺ signals provide the mechanism for fast neuronal-glial signalling at the synaptic level. Since astrocytes can detect chemical transmitters that are released from neurones and can release their own extracellular signals, gliotransmitters, they are intricately involved in homocellular and heterocellular signalling mechanisms in the nervous system. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.     

Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems

During systemic infections, the immune system can signal the brain and act on different neuronal circuits via soluble molecules, such as proinflammatory cytokines, that act on the cells forming the blood-brain barrier and the circumventricular organs. These activated cells release prostaglandin of the E(2) type (PGE(2)), which is the endogenous ligand that triggers the pathways involved in the control of autonomic functions necessary to restore homeostasis and provide inhibitory feedback to innate immunity. Among these neurophysiological functions, activation of the circuits that control the plasma release of glucocorticoids is probably the most critical to the survival of the host in the presence of pathogens. This review revisits this issue and describes in depth the molecular details (including the emerging role of Toll-like receptors during inflammation) underlying the influence of circulating inflammatory molecules on the cerebral tissue, focusing on their contribution in the synthesis and action PGE(2) in the brain. We also provide an innovative view supporting the concept of "fast and delayed response" involving the same ligands but different groups of cells, signal transduction pathways, and target genes.     

Plasticity of central autonomic neural circuits in diabetes

Regulation of energy metabolism is controlled by the brain, in which key central neuronal circuits process a variety of information reflecting nutritional state. Special sensory and gastrointestinal afferent neural signals, along with blood-borne metabolic signals, impinge on parallel central autonomic circuits located in the brainstem and hypothalamus to signal changes in metabolic balance. Specifically, neural and humoral signals converge on the brainstem vagal system and similar signals concentrate in the hypothalamus, with significant overlap between both sensory and motor components of each system and extensive cross-talk between the systems. This ultimately results in production of coordinated regulatory autonomic and neuroendocrine cues to maintain energy homeostasis. Therapeutic metabolic adjustments can be accomplished by modulating viscerosensory input or autonomic motor output, including altering parasympathetic circuitry related to GI, pancreas, and liver regulation. These alterations can include pharmacological manipulation, but surgical modification of neural signaling should also be considered. In addition, central control of visceral function is often compromised by diabetes mellitus, indicating that circuit modification should be studied in the context of its effect on neurons in the diabetic state. Diabetes has traditionally been handled as a peripheral metabolic disease, but the central nervous system plays a crucial role in regulating glucose homeostasis. This review focuses on key autonomic brain areas associated with management of energy homeostasis and functional changes in these areas associated with the development of diabetes.     

Central and Peripheral Cytokines Mediate Immune-Brain Connectivity

The immune system is a homeostatic system that contributes to maintain the constancy of the molecular and cellular components of the organism. Immune cells can detect the intrusion of foreign antigens or alteration of self-components and send information to the central nervous system (CNS) about this kind of perturbations, acting as a receptor sensorial organ. The brain can respond to such signals by emitting neuro/endocrine signals capable of affecting immune reactivity. Thus, the immune system, as other physiologic systems, is under brain control. Under disease conditions, when priorities for survival change, the immune system can, within defined limits, reset brain-integrated neuro-endocrine mechanisms in order to favour immune processes at the expenses of other physiologic systems. In addition, some cytokines initially conceived as immune products, such as IL-1 and IL-6, are also produced in the “healthy” brain by glial cells and even by some neurons. These and other cytokines have the capacity to affect synaptic plasticity acting as mediators of interactions between astrocytes and pre- and post-synaptic neurons that constitute what is actually defined as a tripartite synapse. Since the production of cytokines in the brain is affected by peripheral immune and central neural signals, it is conceivable that tripartite synapses can, in turn, serve as a relay system in immune-CNS communication.     

Interactions between the immune and neuroendocrine systems: clinical implications

The endocrine and immune systems are interrelated via a bidirectional network in which hormones affect immune function and, in turn, immune responses are reflected in neuroendocrine changes. This bidirectional communication is possible because both systems share a common "chemical language" that results from a sharing of common ligands (hormones and cytokines) and their specific receptors. Cytokines are important partners in this crosstalk. They play a role in modulating the hypothalamo-pituitary-adrenal (HPA) axis responses at all three levels: the hypothalamus, the pituitary gland and the adrenals. Acute effects of cytokines are produced at the central nervous system level, particularly the hypothalamus, whereas pituitary and adrenal actions are slower and are probably involved during prolonged exposure to cytokines such as during chronic inflammation or infection. Several mechanisms have been proposed by which peripheral cytokines may gain access to the brain. They include an active transport through the blood-brain barrier, a passage at the circumventricular organ level, as well as a neuronal pathway through the vagal nerve. The immune-neuroendocrine interactions are involved in numerous physiological and pathophysiological conditions and the interactions with the HPA axis may represent a mechanism through which the immune system, by stimulating the production of glucocorticoids, avoids an overshoot of inflammatory response. They may also be involved in the state of hypogonadism, of hypothyroidism and growth inhibition which can occur during inflammatory and infectious diseases. The crosstalk between the immune and endocrine systems is important to homeostasis, since the interactions can produce various appropriate adaptative responses when homeostasis is threatened.     

Neurochemistry of Brain Neuroendocrine Immune System: Signal Molecules

The aim of this review is not so much to show the problem of neuroendocrine, neurophysiologic, and neurochemical mechanisms of the immune system regulation of the organism by brain (there is a great deal of literature about it), as to solve the problem of whether the brain itself is an immune organ, and also to define cellular, neurochemical, and immunological properties of the brain for its immune defense when the blood-brain barrier is not damaged in spite of the penetration of the infection to brain. The accumulated literary data on CNS interaction with the immune system, expression of several cytokines and their receptors in the neurons of human brain culture, in astrocytes and microglia, all testify to the existence of a brain immune system. Recently studies appeared on the expression of major histocompatibility complex in brain neurons. It does not exclude the possibility of expression of immunoglobulins (or immunoglobulin-like proteins) in brain cells. Data obtained by us on the biosynthesis of a number of known interleukins and new cytokines in neurosecretory neurons of hypothalamus (N.Paraventricularis and N. Supraopticus) demonstrate that neuroendocrine nuclei of the hypothalamus are the center for neuroendocrine and immune systems of brain.     

Achieving CNS axon regeneration by manipulating convergent neuro-immune signaling

After central nervous system (CNS) trauma, axons have a low capacity for regeneration. Regeneration failure is associated with a muted regenerative response of the neuron itself, combined with a growth-inhibitory and cytotoxic post-injury environment. After spinal cord injury (SCI), resident and infiltrating immune cells (especially microglia/macrophages) contribute significantly to the growth-refractory milieu near the lesion. By targeting both the regenerative potential of the axon and the cytotoxic phenotype of microglia/macrophages, we may be able to improve CNS repair after SCI. In this review, we discuss molecules shown to impact CNS repair by affecting both immune cells and neurons. Specifically, we provide examples of pattern recognition receptors, integrins, cytokines/chemokines, nuclear receptors and galectins that could improve CNS repair. In many cases, signaling by these molecules is complex and may have contradictory effects on recovery depending on the cell types involved or the model studied. Despite this caveat, deciphering convergent signaling pathways on immune cells (which affect axon growth indirectly) and neurons (direct effects on axon growth) could improve repair and recovery after SCI. Future studies must continue to consider how regenerative therapies targeting neurons impact other cells in the pathological CNS. By identifying molecules that simultaneously improve axon regenerative capacity and drive the protective, growth-promoting phenotype of immune cells, we may discover SCI therapies that act synergistically to improve CNS repair and functional recovery.     

Non-neuronal nicotinic acetylcholine receptors: Cholinergic regulation of the immune processes

Nicotinic acetylcholine receptors (nAChRs) were initially discovered and studied as mediators of fast synaptic transmission in neuromuscular junctions and autonomic ganglia. Later on, they were found in the brain and in many nonexcitable tissues where they regulate vital cellular functions and the activity of other receptors. Primary immune organs, the bone marrow and thymus, are innervated with cholinergic nerves, which mediate the control of lymphopoiesis provided by the autonomic nervous system. In addition, lymphocytes are able to produce endogenous acetylcholine that can regulate the immune processes in an auto/paracrine way. Correspondingly, both T and B lymphocytes express functional nAChRs involved in the regulation of development and activation of these cells. This review describes the structure and roles of nAChRs in the immune system with regard to its potential regulation by the autonomic nervous system, as well as by self sources of endogenous agonists. Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 307–314, July–October, 2007.     

Arginine vasopressin as a central neurotransmitter

Anatomical and electrophysiological studies have revealed a widespread innervation of the brain by arginine vasopressin (AVP)-containing fibers. There is evidence that these central AVP pathways may be activated simultaneously with endocrine pathways. Stimulation of hypothalamic nuclei that contain AVP cell bodies causes changes in electrical activity of neurons in areas receiving AVP projections; in these same regions, release of immunoreactive AVP can be detected in response to appropriate stimuli or hypothalamic stimulation. These parts of the brain have also been shown to contain AVP receptors, and application of AVP to cells in these areas alters spontaneous activity or modifies the responses to other transmitters. AVP appears to act as a neurotransmitter involved in the central control of the cardiovascular, renal, and thermoregulatory systems. AVP may act centrally to coordinate autonomic and endocrine responses to homeostatic perturbations.     

Role of endocannabinoids in brain development.

In addition to those functions that have been extensively addressed in this special issue, such as nociception, motor activity, neuroendocrine regulation, immune function and others, the endogenous cannabinoid system seems to play also a role in neural development. This view is based on a three-fold evidence. A first evidence emerges from neurotoxicological studies that showed that synthetic and plant-derived cannabinoids, when administered to pregnant rats, produced a variety of changes in the maturation of several neurotransmitters and their associated-behaviors in their pups, changes that were evident at different stages of brain development. A second evidence comes from studies that demonstrated the early appearance of elements of the endogenous cannabinoid system (receptors and ligands) during the brain development. The atypical location of these elements during fetal and early postnatal periods favours the notion that this system may play a role in specific molecular events related to neural development. Finally, a third evidence derives from studies using cultures of fetal glial or neuronal cells. Cannabinoid receptors are present in some of these cultured cells and their activation produced a set of cellular effects consistent with a role of this system in the process of neural development. All this likely supports that endocannabinoids, early synthesized in nervous cells, play a role in events related to development, by acting through the activation of second messenger-coupled cannabinoid receptors.     

Bellini, Carpaccio, and receptors in the central nervous system.

With the convergence of science from the fields of neurobiology and immunology, many exciting and challenging surprises have emerged regarding cytokines, neuroendocrine hormones, neuropeptides, excitatory amino acids, and their receptors. For some time neurobiologists have known that subsets of neural cells had different receptors for the same ligand. Those subsets of cells could be as different as neurons and astrocytes and as closely related as astrocytes from different lineages or anatomical areas. The neurobiological puzzle has been to determine the functional meaning of these differences. Immunologists in contrast have long understood the clear cut differences between T and B lymphocytes or T helper/inducer and T cytotoxic/suppressor cells and their response to cytokines. However, it is only very recently that they have discovered preferential use by these cells of different receptors for an identical cytokine ligand. Indeed, identical cytokines in the central nervous system and immune response may induce their pleiotropic responses by utilizing different receptors in these two systems. Immunologic paradigms may help neurobiologists predict the existence of subsets of neural cells and their function. Likewise, neurobiology may enable immunologists to predict roles for receptors in gene families as well as the existence of as yet unidentified receptors.     

Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human immunodeficiency virus type 1.

Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) are produced by leukocytes and play a role in immune responses. They also function in normal brain physiology as well as in pathological conditions within the central nervous system, where they are produced by brain macrophages (microglia) and brain astrocytes. In this study, we document the ability of human immunodeficiency virus type 1 (HIV-1) to induce TNF alpha and IL-1 in primary rat brain cultures. While productive infection did not occur in these cells, it was not required for cytokine induction. Using monocyte/macrophage-tropic (JRFL) and T-cell-tropic (IIIB) strains of HIV-1, we were able to induce cytokines in both microglia and astrocytes. In addition to whole virus, recombinant envelope proteins also induced these cytokines. The induction of IL-1 and TNF alpha could be blocked by a panel of antibodies recognizing epitopes in the gp120 and gp41 areas of the envelope. Soluble recombinant CD4 did not block TNF alpha and IL-1 production. If TNF alpha and IL-1 can be induced in brain tissue by HIV-1, they may contribute to some of the neurologic disorders associated with AIDS.     

Corticotropin releasing hormone and its function in the skin.

The skin, as the largest organ of the body, is strategically located as a barrier between the external and internal environments, being permanently exposed to noxious stressors such as bursts of radiation (solar, thermal), mechanical energy, or chemical and biological insults. Because of its functional domains and structural diversity, the skin must have a constitutive mechanism for dealing with the stressors. Activities of the skin are mostly regulated by local cutaneous factors and stressed skin can generate signals to produce rapid (neural) or slow (humoral) responses to local or systemic levels. Thus, the skin neuroendocrine system is comprised of locally produced neuroendocrine mediators that interact with corresponding specific receptors through para- or autocrine mechanisms. Furthermore, it is known for several years that the corticotropin-releasing hormone (CRH)/ pro-opiomelanocorticotropin (POMC) skin system fulfils analogous functions to the hypothalamic-pituitary-adrenal (HPA) stress axis. Additionally, skin cells produce hormones, neurotansmitters and neuropeptides, having the corresponding receptors and the skin itself is able to fulfill a multidirectional communication between endocrine, immune and central nervous systems as well as other internal organs. In summary, the skin expresses an equivalent of the prominent hypothalamic-pituitary-adrenal stress axis that may act as a cutaneous defense system, operating as a coordinator and executor of local responses to stress, in addition to its normal function: the preservation of body homeostasis.     

Toll信号通路在中枢神经系统损伤中的作用

Toll样受体(Toll-like receptors,TLR)是先天性免疫反应识别病原体的一个重要分子,在免疫系统中发挥关键作用.其家族各种成员的主要功能是识别入侵病原体表面的各种不同分子模式,随后启动免疫反应,达到保护机体作用.在大脑中,小胶质细胞可以作为抗原提呈细胞,参与脑内免疫反应,也可以通过分泌各种促炎症因子启动或促进免疫反应,而TLR家族在中枢神经免疫系统的作用仍存在争议,它既可以通过促进神经免疫反应枢纽因子的表达来增强免疫,也可因免疫过度而损伤神经细胞.总之,Toll信号通路对中枢神经系统疾病有一定的调控作用.     

Role of Neuropoietic Cytokines in Development and Progression of Diabetic Polyneuropathy: From Glucose Metabolism to Neurodegeneration

Diabetic neuropathy develops as a result of hyperglycemia- induced local metabolic and microvascular changes in both type I and type II diabetes mellitus. Diabetic neuropathy shows slower impulse conduction, axonal degeneration, and impaired regeneration. Diabetic neuropathy affects peripheral, central, and visceral sensorimotor and motor nerves, causing improper locomotor and visceral organ dysfunctions. The pathogenesis of diabetic neuropathy is complex and involves multiple pathways. Lack of success in preventing neuropathy, even with successful treatment of hyperglycemia, suggests the presence of early mediators between hyperglycemia-induced metabolic and enzymatic changes and functional and structural properties of Schwann cells (SCs) and axons. It is feasible that once activated, such mediators can act independently of the initial metabolic stimulus to modulate SC-axonal communication. Neuropoietic cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), tumor necrosis factor alpha (TNF-α), and transforming growth factor beta (TGF- β), exhibit pleiotrophic effects on homeostasis of glia and neurons in central, peripheral, and autonomic nervous system. These cytokines are produced locally by resident and infiltrating macrophages, lymphocytes, mast cells, SCs, fibroblasts, and sensory neurons. Metabolic changes induced by hyperglycemia lead to dysregulation of cytokine control. Moreover, their regulatory roles in nerve degeneration and regeneration may potentially be utilized for the prevention and/or therapy of diabetic neuropathy.