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Review Article

NEUROBIOLOGY OF THE STRESS RESPONSE: CONTRIBUTION OF THE SYMPATHETIC NERVOUS SYSTEM TO THE NEUROIMMUNE AXIS IN TRAUMATIC INJURY

Molina, Patricia E

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doi: 10.1097/01.shk.0000167112.18871.5c
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Abstract

INTRODUCTION

Despite considerable advancement in the development of treatment modalities, our understanding of the processes involved in control of inflammatory responses is incomplete. Recently, the importance of neuroendocrine mechanisms has gained recognition, leading to the redefinition of our traditional views of the factors controlling inflammatory responses. Because uncontrolled as well as impaired inflammatory responses can lead to deleterious outcomes, it is imperative to develop the appropriate knowledge base and conceptualization of the control mechanisms involved. Inflammatory responses are not exclusive to chronic or infectious conditions, but have also been identified after acute stress such as that resulting from traumatic injury. Among the etiological factors directly involved in triggering the proinflammatory response associated with traumatic injury are tissue hypoperfusion, hypoxia, infection, and burn (1, 2).

The contribution of neuroendocrine mechanisms to the dynamic regulation of the magnitude and tissue specificity of inflammatory responses has been recognized by several investigators. Considerable attention has been given to the effectiveness of parasympathetic nerve stimulation in suppressing the magnitude of the proinflammatory response, leading to coining of the term “inflammatory reflex” (3). Interestingly, the stress response to injury is associated with suppressed parasympathetic nervous system activity and prevalence of the activation of the other arm of the autonomic nervous system-the sympathetic nervous system. Furthermore, systemic and tissue release of norepinephrine and epinephrine, the principal neurotransmitters of the sympathetic nervous system, exert marked cellular responses on cells of the immune system. Thus, as we increase our understanding of the role of neuronal pathways in modulating the inflammatory response, it is important to integrate the role and contribution of both arms of the autonomic nervous system in the regulation of the inflammatory responses.

Dissecting the relative contribution of the sympathetic nervous system to modulation of immune responses during traumatic injury requires an analysis of conditions under which this arm of the autonomic nervous system is activated: its anatomical interactions with immune competent cells and the functional consequences of this interaction as they affect the regulation of the host response. We begin by providing an overview of the neurobiology of the stress response, and we go on to describe how the organism responds to stress and the neurocircuitry that is involved, as well as how the efferent autonomic and neuroendocrine pathways involved in mediating the peripheral responses to stress modulate immune function.

CONDITIONS UNDER WHICH THE SYMPATHETIC NERVOUS SYSTEM IS LIKELY TO BE INVOLVED IN CONTROL OF INFLAMMATION

Alterations in the environment or acute insults to an individual that require adaptation involve the synchronized interaction of multiple neuronal and endocrine pathways geared at restoring homeostasis and ensuring the fundamental survival, growth, and reproductive functions of the host (Fig. 1). The integrated hemodynamic, metabolic, behavioral, and immune responses that allow adaptation of the host are referred to as the stress response (4). Central to the integration of this reflex neuroendocrine response are the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Their activation in response to stress is centrally integrated, particularly at the level of the periventricular nucleus of the hypothalamus and the locus ceruleus. In parallel to activation of the SNS response, the parasympathetic nervous system tone responsible for vegetative functions is suppressed. Several additional neuroendocrine pathways are simultaneously activated, which, in turn, form redundant and feedback circuits (feed-forward or negative feedback), contributing to a synchronized cascade of efferent neuroendocrine signals targeted to increase the host's ability to respond to the stress signal. Despite the multiple and intricate interconnected pathways, the two pathways at the core of the stress system wiring are the HPA axis and the SNS system.

Fig. 1
Fig. 1:
Core stress system wiring. Tissue injury and hemorrhagic shock signal the central nervous system (CNS), activating the two core systems; the HPA axis and the SNS involved in orchestrating counterregulatory responses. Activation of the HPA axis results in release of glucocorticoids from the adrenal cortex into the systemic circulation. Activation of the SNS results in release of epinephrine and norepinephrine from the adrenal medulla and direct localized tissue release of norepinephrine from sympathetic nerve terminals. The ultimate purpose of this stress response activation is to restore cardiovascular and hemodynamic stability, to mobilize stored energy sources to sustain the increased metabolic demands of the host, and to ensure that immune competence and tissue repair can proceed. In parallel to activation of the sympathetic arm of the autonomic nervous system, activity of the parasympathetic nervous system, responsible for control of vegetative functions, is suppressed.

The core function of the HPA and SNS pathways is central to the host's adaptation to acute challenges by ensuring energy substrate mobilization, cardiovascular and hemodynamic compensation, increasing awareness, and subsequently by contributing to host immune function and tissue repair (5). Signals sent to other brain regions, including those that are not directly involved in the immediate restoration of vital functions during acute stress, affect additional behavioral and physiological responses such as sleep, growth, reproduction, and mood. Although the short-term activation of these stress response mechanisms is vital by providing substrate availability to sustain increased metabolic demands of the individual, prolonged duration and increased magnitude of their activity leads to deleterious effects on metabolism (6), immune function (7), reproduction (8), and cardiovascular function (9). Similarly deleterious is the impaired activation or lack of responsiveness of the HPA and autonomic nervous systems, as in the case of the critically ill patient. Thus, the overall appropriate and controlled activation and termination of the neuroendocrine responses that mediate the necessary physiological functions involved in maintaining and restoring homeostasis in the event of illness, trauma, surgery, or fasting are of critical importance.

Using hemorrhagic shock as a model of acute stress, one can dissect the role of the SNS and identify its role as a key component of the neuroendocrine response to stress (Fig. 1). The hemorrhage-induced decreases in mean arterial blood pressure lead to decreased stretch of the baroreceptors in the carotid sinus and aortic arch this decreased firing from baroreceptors initiates afferent signals to the CNS. These afferent signals include visceral peptidergic projections (to oxytocin neurons in the hypothalamus), and signals from the nucleus tractus solitarius relayed via A1 (noradrenergic) and C1 (adrenergic) cells of the ventrolateral medulla (targeting hypothalamic arginine vasopressin and corticotrophin-releasing hormone [CRH] neurons). Additional afferent signals to the hypothalamus are relayed through neurotransmitters other than catecholamines, including glutamate and γ-amino butyric acid. The integration of these afferent signals occurs predominantly at the level of the periventricular nucleus (10), triggering a cascade of intra- and extrahypothalamic neurochemical events. These signals are relayed via classical transmitters, as well as numerous neuropeptides, including CRH, opioids, neuropeptide Y and galanin, and gaseous neuromodulators like nitric oxide and carbon monoxide, many of which are colocalized with classical transmitters and may act in concert with them at the level of individual PVN neurons. Clearly, multiple neurochemical pathways are simultaneously activated and integrated during the compensatory response to acute blood loss.

In parallel to central relay signals dictating the CNS response to acute stress, descending autonomic visceromotor (11) (brainstem and spinal projections) cell groups (12) are activated as well (Fig. 1). The resulting efferent or descending signals are primarily directed to restoring hemodynamic and metabolic homeostasis, ensuring adequate perfusion and oxygenation of tissues, as well as energy substrate mobilization to sustain the increased demands of the organism during this “fight or flight” response. These descending projections control heart rate and blood pressure (13) and make contact with sympathetic and parasympathetic preganglionic neurons in the intermediolateral nucleus of the thoracic and lumbar spinal cord. In addition, these neuronal pathways are capable of stimulating cells of the immune system directly through neurotransmitter release in the parenchyma of lymphoid organs (14), and indirectly through neurotransmitter and hormonal release into the circulation. Several lines of evidence indicate that these neurotransmitters and neuromodulators exert significant effects on the inflammatory/immune response, affecting the ability of the host to repair tissue damage and produce an adequate host defense from infections. Thus, descending autonomic neuronal pathways control vital hemodynamic and metabolic functions while also modulating several aspects of the immune system.

THE CNS SIGNALS THE IMMUNE SYSTEM THROUGH NEURONAL AND HORMONAL PATHWAYS

Catecholamines are among the neurotransmitters that affect immune responses humorally through circulating adrenal-derived epinephrine, as well as locally through neuronal release of norepinephrine. Studies have provided anatomical evidence of CNS-lymphoid organ connection through autonomic and sensory fibers in immune tissues such as the bone marrow, thymus, spleen, and lymph nodes (Fig. 2). This sympathetic innervation of lymphoid organs is found across species and has been confirmed by specific immunohistochemistry for tyrosine hydroxylase. In the bone marrow, myelinated and nonmyelinated fibers with immunoreactivity to tyrosine hydroxylase, vasoactive intestinal peptide, and neuropeptide Y are distributed with vascular plexuses where they may influence hemopoiesis and cell migration (15). In the lungs, noradrenergic nerve fibers supply tracheobronchial smooth muscle and glands. In addition, nerve fibers have also been demonstrated throughout the different compartments of bronchus-associated lymphoid tissue, e.g., under the epithelium, in the smooth muscle layer, along the vasculature, and between immune cells of bronchus-associated lymphoid tissue parenchyma, forming close contacts with mast cells, cells of the macrophage/monocyte lineage, and/or other lymphoid cells (16). In the thymus, noradrenergic nerve fibers have been localized in the subcapsular, cortical, and corticomedullary regions, associated with blood vessels and intralobular septa, occasionally branching into the cortical parenchyma where they reach close proximity to thymocytes.

Fig. 2
Fig. 2:
Sympathetic innervation of immune tissues. CNS-lymphoid organ connections through autonomic and sensory fibers in tissues like spleen, bone marrow, thymus, and lymph nodes provide neuromodulation of cellular responses, including hemopoiesis, cell migration, and cytokine production. Adrenergic neurotransmitters can affect immune cell function through endocrine (adrenal-derived catecholamines) or paracrine (sympathetic nerve terminal-derived norepinephrine) mechanisms. Cellular responses are adrenergic receptor specific with suppressive effects predominantly mediated through β-adrenergic receptors, with the adrenergic receptor type having wider expression in cells of the immune system.

Among the organs that have received the most attention because of the technical feasibility of surgical and chemical manipulation to investigate the role of neuroimmunomodulation is the spleen. Fluorescence histochemistry has demonstrated noradrenergic nerve fibers entering the spleen with the splenic artery and then further distributing with the central artery, with the capsular and trabecular systems, and into the parenchyma where they distribute among T lymphocytes and along a macrophage zone at the marginal sinus. The origin of sympathetic neural innervation in rat spleen is predominantly the superior mesenteric/celiac ganglion. More recent and sophisticated techniques have allowed visualization of noradrenergic fiber distribution into B cell follicles, particularly during development. Thus, T and B lymphocytes as well as macrophages have been identified to be located at sites adjacent to tyrosine hydroxylase-positive nerve fibers, where they are exposed to neuronal norepinephrine release (17). Similar patterns of innervation have been described for cervical, mesenteric, and popliteal lymph nodes, as well as Peyer's patch and lymphoid tissue associated with the appendix. Noradrenergic nerves have been visualized entering the lymph nodes at the hilus with the vasculature and distributed throughout the medullary cords among mixed populations of lymphocytes and macrophages, and in the subcapsular region. These fibers contribute to innervation of the paracortical and cortical regions, regions abundant with T lymphocytes. In addition to the innate distribution of neuronal fibers in close proximity with cells of the immune system, the local production of neuropeptides by cells of the immune system has also been recognized as a mechanism through which neuroimmunomodulation of localized inflammation can take place (18). The enzymatic capacity of immune cells to synthesize, store, and release neurotransmitters like norepinephrine has added an autocrine neuroimmune mechanism not considered in this review, but worth further investigation.

Thus, in lymphoid tissues, lymphocytes and macrophages are located at sites adjacent to neuronal fibers, exposing them to local release of neuropeptides forming synaptic-like neuroimmune interactions, allowing modulation of localized inflammatory responses through direct neural release and humoral neuroendocrine mediators. The local release of neuroendocrine mediators coupled with specific receptor expression in immune cells establishes a functional neuroimmune connection capable of modulating various responses, including cytokine production, neutrophil chemotaxis, phagocytosis, and reactive oxygen species production and release.

WHAT IS THE FUNCTIONAL SIGNIFICANCE OF THESE NEUROENDOCRINE-IMMUNE INTERACTIONS?

The functional significance of neuroimmune synaptic interactions has been demonstrated by several studies. Catecholamines and adrenergic agonists in particular have been demonstrated to exert important regulatory functions on macrophages as well as on B and T lymphocyte cytokine production, proliferation, and antibody secretion (19). In vivo studies have shown that catecholamines affect dendritic cell function, enhancing myelopoiesis and suppressing lymphopoiesis through specific adrenergic receptor mechanisms (20). In vitro studies have demonstrated that catecholamines inhibit lipopolysaccharide (LPS)-induced macrophage production of tumor necrosis factor (TNF) (21), interleukin (IL)-12 (22), and macrophage inhibitory protein 1α (23) and enhance LPS-stimulated release of IL-10 (24), while suppressing nitrite production (25). The contribution of adrenergic regulation of cytokine production is also evident by the increased TNF-α production by peritoneal macrophages obtained from sympathectomized mice (26).

The conclusions reached by some studies appear to be conflictive, part of which can be explained by differential effects mediated by the specific receptor subtypes, as well as by the differential cellular response. Catecholamines act on their target cells through binding to cell surface adrenergic receptors. Reports indicate that α- and β-adrenergic receptors are expressed in immune cells, with β-adrenergic receptors having a wider expression in these cells (27). β-Adrenergic receptors belong to the family of G protein-coupled receptors that when activated by ligand binding, lead to elevation of intracellular cAMP and activation of protein kinase A. Like other ligand-mediated cAMP elevations, catecholamines suppress TNF, IL-1, and IL-6, and enhance IL-10 production via this mechanism. In contrast, results from in vitro experiments indicate that catecholamine effects mediated through α-adrenergic receptors can enhance TNF message and IL-12 expression (28). Given that expression of β-adrenergic receptors predominates in cells of the immune system, adrenergic effects would favor an anti-inflammatory effect over one of proinflammation. However, overall, it would be an in vivo systemic response that would provide more relevant information on the contribution of the sympathetic nervous system to control of inflammation.

The overall suppressive effect of norepinephrine in proinflammatory mediator release has been demonstrated in studies conducted in our laboratory in which alveolar- and spleen-derived macrophages isolated from naive rats were challenged with LPS in the presence of norepinephrine (10 nM). In this setting, adrenergic stimulation resulted in marked suppression of LPS-induced TNF release from both cell types. Other laboratories have observed similar anti-inflammatory effects of norepinephrine on astrocyte activation and production of TNF (29). Additional mechanisms to that of suppression of cytokine production were identified in those studies. Removal of norepinephrine resulted in enhanced amyloid-induced inflammation attributed to decreased intracellular IκB. Overall, noradrenergic depletion potentiated β-amyloid-induced cortical inflammation and neuronal cell death (30), providing evidence that the role of noradrenergic innervation is not limited to control of an acute inflammatory response.

The functional effects of catecholamines on cells of the immune system have been confirmed in healthy human volunteers (31). Furthermore, the relevance of this control mechanism and the implications for its dysregulation have been demonstrated by the rapid systemic release of IL-10 and the high incidence of infection in patients with “sympathetic storm” from acute accidental or iatrogenic brain trauma (32). Similar stress-induced induction of IL-10 expression has been reported for myocardial infarction patients and after traumatic brain injury. Several investigators have documented the exaggerated SNS activation during these periods of critical illness, particularly in patients with head injury. Although the detrimental effects of sustained and exaggerated SNS activation on cardiovascular and metabolic homeostasis have been recognized, attention should be brought to the likelihood of immune dysregulation as well. Moreover, the potential immunomodulatory effects of pharmacotherapy used in these critically ill patients needs to be further examined (33).

Thus, sympathoexcitatory pathways exert direct effects on cells of the immune system affecting cytokine expression, lymphocyte function, and cytotoxic activity (Fig. 2). In addition, as described below, the cells of the immune system as well as the inflammatory mediators released by them communicate with the CNS through direct and indirect mechanisms.

THE IMMUNE SYSTEM COMMUNICATES TO THE CNS, FORMING A FEEDBACK LOOP

The neuroimmune bidirectional network is comprised of a descending pathway that links the CNS to peripheral immune tissues and a parallel afferent arm linking the immune system with the CNS. The integrity of this loop allows for communication between the CNS and the peripheral immune system, integrating neuronal and immune signals in the periphery as well as in the CNS. The synaptic-like neural connection with lymphoid tissues modulates multiple cellular processes in the immune system through the local release of neuropeptides, neurotransmitters, and neurohormones. Cells from the immune system express functional receptors and the respective signal-transduction pathway components for several neuroendocrine mediators, allowing cellular functional responses to agonist stimulation. Similarly, cells in the CNS are capable of synthesizing, secreting, and responding to inflammatory and immune-related molecules. There is considerable evidence that the peripheral immune system can signal the brain to elicit a sickness response during infection and inflammation (Fig. 3). Peripheral immune molecules such as cytokines influence CNS actions (34) through various mechanisms, including cytokine entry into the brain through a saturable transport mechanism or through areas that lack the blood-brain barrier as well as through activation of afferent neurons of the vagus nerve. Although active transport is required for some cytokines to enter the brain (35), others gain access into the brain through fenestrated capillaries in different regions of the CNS. These sites are relatively devoid of a blood-brain barrier such as the structures lining the anteroventral border of the third ventricle, including the organum vasculosum of the lateral terminalis and subfornical organ, the median eminence, and the posterior lobe of the pituitary. Their capillaries do not form tight junctions and are thus far more readily penetrable via the paracellular route. Passage of cytokines through these areas is thought to produce localized effects in neuronal structures in the immediate vicinity directly or indirectly (36). Thus, CNS signaling by cytokines may not even require their active transport into the CNS. Signaling may be relayed through classical neurotransmitters or through lipid mediators produced and released in these areas devoid of the blood-brain barrier. Brain microvessels have been shown to respond to cytokine stimulation by producing prostaglandins (PGE2), which can then in turn affect CNS neurotransmission. Other investigators have shown that there is a median eminence site of action at which peripherally stimulated IL-6 possesses CRH-releasing activity. Additionally, evidence suggests that the peripheral production of proinflammatory cytokines may signal the brain through stimulation of vagal afferents (37). Vagal afferent signaling by peripheral immune mediators has been documented to contribute to HPA activation, fever, sleep, norepinephrine turnover, and sickness behavior (38, 39). The mechanisms involved in the interaction between peripheral cytokines and vagal fibers is still under investigation. Functional cytokine receptors have not been identified in abdominal vagal afferents. However, abdominal paraganglia, which are in close proximity to and synapse with vagal fibers, specifically bind biotinylated IL-1ra. Moreover, localized perivagal cytokine production by may also contribute to this signaling mechanism (40). Thus, several mechanisms can be identified that are participant of the signaling from the peripheral immune system to the CNS, closing the bidirectional neuroendocrine loop.

Fig. 3
Fig. 3:
Afferent signals from the peripheral immune system to the CNS. With several mechanisms involved in signaling from the peripheral immune system to the CNS, closing the bidirectional neuroendocrine loop can be identified. Among the mechanisms that involved in cytokine-mediated influence on CNS actions are cytokine entry into the brain through a saturable transport mechanism (a) or through areas that lack the blood-brain barrier (b) as well as through activation of afferent neurons of the vagus nerve (c). Vagal afferent signaling by peripheral immune mediators has been documented to contribute to HPA activation, fever, sleep, norepinephrine turnover, and sickness behavior. CNS signaling by cytokines may not even require their transport into the CNS and can be relayed through classical neurotransmitters or lipid mediators in regions like the median eminence.

How these are affected during injury and disease has not been fully investigated. However, several lines of evidence would suggest that pathological conditions would be likely to alter blood-brain barrier permeability, enhancing the access of peripheral immune cells or their products to the CNS (41). This afferent signaling pathway to the CNS in response to peripheral inflammatory challenges functions as a feedback mechanism modulating behavioral and biological responses during disease (Fig. 4). This bidirectional neuroimmune interaction creates a circuit of responses that can be considered an inflammatory reflex because of the immediate effects produced by the release of these neuroendocrine and immune mediators into the periphery, as well as the ability of the CNS of rapidly integrating afferent signals conducted by peripheral nerves. The integrity of such circuit is critical in host protection and adaptation to systemic challenges such as traumatic injury and infection.

Fig. 4
Fig. 4:
Reflex arch of bidirectional communication. The neuroimmune bidirectional network is comprised of a descending pathway that links the CNS to peripheral immune tissues, and a parallel afferent arm linking the immune system with the CNS. The synaptic-like neural connection with lymphoid tissues modulates multiple cellular processes in the immune system through the local release of neuropeptides, neurotransmitters, and neurohormones. In turn, the peripheral immune system mediators (i.e., cytokines and chemokines) communicate with the CNS through stimulation of sensory and vagal afferents or by crossing the blood brain barrier, allowing easy access to the median eminence and hypothalamo-pituitary structures; that, in turn, responds by activating descending autonomic and neuroendocrine pathways. Moreover, these immune-derived mediators contribute to development of sickness behavior during infection and inflammation. The integrity of this loop allows for communication between the CNS and the peripheral immune system, integrating neuronal and immune signals in the periphery as well as in the CNS. Thus, the system is designed in a manner similar to a feedback loop in which direct neural activation of lymphoid tissues effects cellular responses, forming a reflex arch that is characterized by bidirectional communication.

RELEVANCE OF THE NEUROIMMUNE REFLEX

Understanding the relevance of neuroimmunomodulation to overall control of inflammatory responses during specific pathological conditions requires a model that resembles a clinical presentation in which the nervous system as well as the immune system are challenged accordingly and in which the outcome from neuroimmune interaction affects the host response. Studies in our laboratory have used hemorrhagic shock in conscious, unrestrained rodents to elucidate the contribution of the SNS to modulation of host response. This model allows for the determination of neuroendocrine activation and the concordant inflammatory response of the host in the absence of anesthetics or sedatives that can alter the efferent neural pathways that are immediately triggered by hypotension and that mediate the restoration of hemodynamic, metabolic, and host defense counterregulatory responses.

Controlled inflammation during a period after injury is essential for tissue repair and maintenance of immune competence (42). The regulated initiation and termination of this tissue proinflammatory response is under neuroendocrine control through direct neurotransmitter release at the target organ, as well as indirectly through humoral factors, including catecholamines, neuropeptides, and glucocorticoids among a few. Although the early post-traumatic inflammatory response is directed to repair tissues and establish immune competence, an increased magnitude and duration of this response is associated with delayed restoration of homeostasis and increased tissue injury leading to multiple organ failure (43). Several lines of evidence indicate that the early proinflammatory cytokine upregulation contributes to the development of this syndrome by synergistic actions or by priming or predisposing the host to subsequent injury. Thus the pro/anti-inflammatory cytokine balance, which should mediate tissue repair and recovery, if uncontrolled, can produce tissue injury on one spectrum and immunosuppression on the other extreme (44). Hence, the relevance of understanding the mechanisms involved in control of the magnitude and duration of this response.

NEUROIMMUNOMODULATION IN STRESS

The counter-regulatory response to acute and prolonged illness involves the release of catecholamines in high concentrations into the systemic circulation through the sympathoadrenal activation as well as into specific tissue beds through noradrenergic discharge from sympathetic nerve terminals (45). This activation of the SNS is much more evident under conditions of acute traumatic injury, particularly those involving the brain (46). Our working hypothesis is that this sudden and massive release of circulating and tissue catecholamines can affect the magnitude of tissue cytokine response and, consequently, can impact the integrity of subsequent host defense mechanisms. Several clinical observations would support this association. However, demonstration of the role of the SNS in regulation of immune responses during injury is best done in an experimental setting. Using traumatic injury as a trigger for moderate inflammation, we have examined the contribution of tissue norepinephrine content to the inflammatory response after hemorrhagic shock in chronically instrumented conscious unrestrained rodents.

NORADRENERGIC SUPPRESSION OF THE HEMORRHAGE-INDUCED INCREASE IN LUNG TNF

To test the role of tissue norepinephrine, animals were chronically pretreated with small doses of the neurotoxin 6-hyroxy-dopamine (6-OHDA) before hemorrhagic shock (47). Once accumulated in neurons, 6-OHDA undergoes auto-oxidation, causing the degeneration of catecholamine-containing neurons. Enhanced specificity for noradrenergic neurons is achieved through repeated small dose administration. Because 6-OHDA does not penetrate through the blood-brain barrier, the effects of its peripheral administration can be attributed to peripheral noradrenergic nerve endings. Noradrenergic tone was effectively removed by the destruction of noradrenergic nerve terminals, manifested by depletion of norepinephrine stores (80%-90%) in peripheral tissues, including lung and spleen. This removal of tissue norepinephrine stores resulted in an exacerbated rise in lung TNF expression after hemorrhagic shock and fluid resuscitation. These results strongly suggested that during the acute stress produced by hemorrhagic shock, control of the early proinflammatory response is partly under suppressive effects of localized noradrenergic tone. Because norepinephrine is the predominant neurotransmitter released from postganglionic sympathetic nerve terminals, these studies provided evidence of SNS contribution to the regulation of the magnitude of the early proinflammatory response to injury.

Other investigators have reported similar exacerbation of the inflammatory response after liver injury in chemically sympathectomized mice (48). Moreover, studies by Le Tulzo et al. (1) have demonstrated that β-adrenergic blockade increased hemorrhage-induced NF-κB activation and enhanced the hemorrhage-induced proinflammatory cytokine expression in the lung. Evidence supporting a direct anti-inflammatory effect of sympathetic nerve stimulation on cellular responses has been provided by in vitro studies in isolated perfused spleens. In this setting, electrical stimulation of sympathetic nerves inhibits stimulated TNF secretion via β-adrenergic pathways (49). Taken together, these data suggest that overall, tissue norepinephrine exerts anti-inflammatory effects, serving as a “brake” in the inflammatory cascade, controlling and regulating the magnitude and profile of cytokine responses. Thus, activation of the SNS (autonomous in the case of hemorrhagic shock and stimulated in the case of electrical stimulation) suppresses tissue proinflammatory responses.

The adrenergic effects on immune function appear to be differentially mediated by the specific adrenergic receptor subtypes. The anti-inflammatory effects of norepinephrine appear to be mediated via β2-adrenergic receptors. Le Tulzo et al. (1) showed that although β-blockade enhanced lung proinflammatory cytokine expression, contrasting effects were observed after α-adrenergic antagonist administration before hemorrhagic shock. Their results indicate that α-adrenergic blockade prevents the elevation in mRNA levels of IL-1α, TNF-α, and TGF-β1, the increase in IL-1β protein, as well as the activation of nuclear factor (NF)-κB in intraparenchymal pulmonary mononuclear cells produced by blood loss. Those results suggested that although adrenergic stimulation through the α-adrenergic receptor favored a proinflammatory response, stimulation through the β-adrenergic receptor suppressed or controlled inflammation. This concept of balanced adrenergic control of cytokine production dependent on the specific adrenergic receptor is supported by studies in isolated perfused liver. In this setting, norepinephrine upregulates TNF production and induces IL-12 through α2-adrenergic receptor-mediated mechanisms (50). These were intriguing findings and their interpretation was complex, as Le Tulzo's (1) studies were performed in anesthetized mice, potentially affecting neural activation during hemorrhage. Furthermore, no assessment was made of the impact of adrenergic blockade on the hemodynamic response to blood loss, a potentially confounding factor to the magnitude of tissue hypoperfusion and thus localized regulation of tissue responses.

Dissecting the contribution of the specific adrenergic receptors involved in modulating proinflammatory responses to hemorrhagic shock is not simple. Results from our studies suggest that the distinction between the adrenergic receptor modulation of tissue cytokine production after hemorrhage can not be clearly demarcated in an in vivo, unanesthetized rodent model of fixed pressure hemorrhage. In vivo administration of adrenergic antagonists can effectively alter the hemodynamic response to blood loss and can affect the severity of the hypotensive response achieved by removal of a given blood volume. Studies from our laboratory show that propranolol pretreatment (1 mg/kg 30 min prehemorrhage) does not produce significant alteration in the tissue expression of TNF, IL-6, and IL1α after hemorrhagic shock and fluid resuscitation. Furthermore, no marked alterations in the hemodynamic response to blood loss and fluid resuscitation were observed in those studies. In contrast, pretreatment with the α-adrenergic receptor antagonist phenoxybenzamine (2.5 mg/kg) before hemorrhagic shock did not produce significant alteration in the magnitude of the tissue cytokine response observed. However, it significantly lowered the blood volume removed required to produce hypotension (mean arterial blood pressure of 40 mmHg). Therefore, α-adrenergic blockade resulted in comparable hemorrhage-induced upregulation in tissue cytokine expression to that elicited by greater blood loss.

Taken together, these results led to the conclusion that depletion of tissue noradrenergic stores removes the inhibitory control on hemorrhage-induced TNF upregulation in the lung. Interestingly, this effect does not appear to be indiscriminate, as no upregulation in IL-6 response was observed in chemically sympathectomized hemorrhaged animals. In contrast, α-adrenergic receptor antagonist-pretreated animals showed an accentuated lung IL-6 response to a given blood loss without affecting the magnitude of the TNF response. Overall, these observations indicate that sympathetic regulation exerts differential adrenergic receptor-mediated effects affecting the balance of cytokine profile expression, supporting a role for sympathetic regulation of immediate tissue cytokine responses to hemorrhagic shock. We speculate that because of the central role of SNS activation during the immediate response to injury, neuroimmune modulation mediated by the SNS during hemorrhagic shock is likely to affect outcome during the postinjury period.

CONCLUSION

SNS activation is central to the integrated stress response. The SNS has significant anatomical and functional interaction with cells of the immune system and plays an important role in control of the magnitude of early inflammatory response to injury by ensuring expression of adequate cytokine balance. These sympathetic neural pathways exert direct effects on cells of the immune system, affecting cytokine expression, lymphocyte function, and cytotoxic activity. In turn, the inflammatory mediators released communicate with the CNS through stimulation of sensory and vagal afferents or by crossing the blood-brain barrier through active transport mechanisms or by taking advantage of areas with fenestrated capillaries, allowing easy access to the median eminence and hypothalamo-pituitary structures. In the CNS, these immune-derived mediators such as cytokines and chemokines modulate neurotransmission, affecting activation of descending autonomic and neuroendocrine pathways (Fig. 4). Thus, the system is designed as a neuroendocrine-immune feedback loop in which direct neural activation of lymphoid tissues effects cellular responses, forming a reflex arch, and establishing bidirectional communication.

REFERENCES

1. Le Tulzo Y, Shenkar R, Kaneko D, Moine P, Fantuzzi G, Dinarello CA, Abraham E: Hemorrhage increases cytokine expression in lung mononuclear cells in mice. J Clin Invest 99:1516-1524, 1997.
2. Molina PE, Malek S, Lang CH, Qian L, Naukam R, Abumrad NN: Early organ-specific hemorrhage induced increases in tissue cytokine content: associated neuro-hormonal and opiate alterations. J Neuroimmunomod 4:28-36, 1997.
3. Tracey KJ: The inflammatory reflex. Nature 420:853-859, 2002.
4. Selye H: A syndrome produced by diverse nocuous agents. Nature 138:13832-13836, 1936.
5. Chrousos GP: Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann N Y Acad Sci 30:311-335, 1998.
6. Chrousos GP: The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes. Int J Obes Relat Metab Disord 24(Suppl 2):S50-S55, 2000.
7. Rozlog LA, Kiecolt-Glaser JK, Marucha PT, Sheridan JF, Glaser R: Stress and immunity: implications for viral disease and wound healing. J Periodontol 70:786-792, 1999.
8. Chatterton RT: The role of stress in female reproduction: animal and human considerations. Int J Fertil 35:8-13, 1990.
9. Bjorntorp P: Stress and cardiovascular disease. Acta Physiol Scand Suppl 640:144-148, 1997.
10. Swanson LW, Sawchenko PE: Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology 31:410-417, 1980.
11. Badoer E, Merolli J: Neurons in the hypothalamic paraventricular nucleus that project to the rostral ventrolateral medulla are activated by haemorrhage. Brain Res 791:317-320, 1998.
12. Porter JP, Brody MJ: Neural projections from paraventricular nucleus that subserve vasomotor functions. Am J Physiol 248:R271-R281, 1985.
13. Zerbe RL, Bayorh MA, Feuerstein G: Vasopressin: an essential pressor factor for blood pressure recovery following hemorrhage. Peptides 3:509-514, 1982.
14. Felten DL: Direct enervation of lymphoid organs: substrate for neurotransmitter signaling of cells of the immune system. Neuropsychobiology 28:110-112, 1993.
15. Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S: Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol 135(2 Suppl):755s-765s, 1985.
16. Nohr D, Weihe E: The neuroimmune link in the bronchus-associated lymphoid tissue (BALT) of cat and rat: peptides and neural markers. Brain Behav Immun 5:84-101, 1991.
17. Meltzer JC, Grimm PC, Greenberg AH, Nance DM: Enhanced immunohistochemical detection of autonomic nerve fibers, cytokines and inducible nitric oxide synthase by light and fluorescent microscopy in rat spleen. J Histochem Cytochem 45:599-610, 1997.
18. Cabot PJ, Carter L, Gaiddon C, Zhang Q, Schafer M, Loeffler JP, Stein CJ: ir-END released from circulating and lymph node-derived lymphocytes of FCA-treated rats. J Clin Invest 100:142-148, 1997.
19. Madden KS, Sanders VM, Felten DL: Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu Rev Pharmacol Toxicol 35:417-448, 1995.
20. Maestroni GJ: Short exposure of maturing, bone marrow-derived dendritic cells to norepinephrine: impact on kinetics of cytokine production and Th development. J Neuroimmunol 129:106-114, 2002.
21. Severn A, Rapson NT, Hunter CA, Liew FY: Regulation of tumor necrosis factor production by adrenaline and β-adrenergic agonists. J Immunol 148:3441-3445, 1992.
22. Hasko G, Szabo C, Nemeth ZH, Deitch EA: Dopamine suppresses IL-12 p40 production by lipopolysaccharide-stimulated macrophages via a β-adrenoceptor-mediated mechanism. J Neuroimmunol 122:34-39, 2002.
23. Hasko G, Shanley TP, Egnaczyk G, Nemeth ZH, Salzman AL, Vizi ES, Szabo C: Exogenous and endogenous catecholamines inhibit the production of macrophage inflammatory protein (MIP) 1α via a β-adrenoceptor mediated mechanism. Br J Pharmacol 125:1297-1303, 1998.
24. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF: Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin 10 production during human endotoxemia. J Clin Invest 97:713-719, 1996.
25. Zinyama RB, Bancroft GJ, Sigola LB: Adrenaline suppression of the macrophage nitric oxide response to lipopolysaccharide is associated with differential regulation of tumour necrosis factor-α and interleukin-10. Immunology 104:439-446, 2001.
26. Chelmicka Schorr E, Kwasniewski MN, Czlonkowska A: Sympathetic nervous system and macrophage function. Ann N Y Acad Sci 650:40-45, 1992.
27. Madden KS, Sanders VM, Felten DL: Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu Rev Pharmacol Toxicol 35:417-448, 1995.
28. Zhou M, Yang S, Koo DJ, Ornan DA, Chaudry IH, Wang P: The role of Kupffer cell α(2)-adrenoceptors in norepinephrine-induced TNF-α production. Biochim Biophys Acta 27:49-57, 2001.
29. Heneka MT, Gavrilyuk V, Landreth GE, O'Banion MK, Weinberg G, Feinstein DL: Noradrenergic depletion increases inflammatory responses in brain: effects on IκB and HSP70 expression. J Neurochem 85:387-398, 2003.
30. Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E: Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int 41:357-365, 2002.
31. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF: Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin 10 production during human endotoxemia. J Clin Invest 97:713-719, 1996.
32. Woiciechowsky C, Asadullah K, Nestler D, Eberhardt B, Platzer C, Schöning B, Glöckner F, Lanksch WR, Volk HD, Döcke WD: Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 4:808-813, 1998.
33. Oberbeck R: Therapeutic implications of immune-endocrine interactions in the critically ill patients. Curr Drug Targets Immune Endocr Metabol Disord 4:129-139, 2004.
34. Rivest S: How circulating cytokines trigger the neural circuits that control the hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology 26:761-788, 2001.
35. Banks WA, Kastin AJ, Broadwell RD: Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 2:241-248, 1995.
36. Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N: How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med 223:22-38, 2000.
37. Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, Watkins LR: Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci 20:49-59, 2000.
38. Sehic E, Blatteis CM: Blockade of lipopolysaccharide-induced fever by subdiaphragmatic vagotomy in guinea pigs. Brain Res 726:160-166, 1996.
39. Kapas L, Hansen MK, Chang HY, Krueger JM: Vagotomy attenuates but does not prevent the somnogenic and febrile effects of lipopolysaccharide in rats. Am J Physiol 274:R406-R411, 1998.
40. Goehler LE, Gaykema RPA, Nguyen KT, Lee JE, Tilders FJH, Maier SF, Watkins LR: Interleukin-1β in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J Neurosci 19:2799-2806, 1999.
41. Brown KA: Factors modifying the migration of lymphocytes across the blood-brain barrier. Int Immunopharmacol 1:2043-2062, 2001.
42. Stephan RN, Ayala A, Chaudry IH: Monocyte and lymphocyte responses following trauma. In Schlag G, Redl H (ed): Pathophysiology of Shock, Sepsis and Organ Failure. Berlin: Springer-Verlag, 1993, pp 131-144.
43. Faist E, Baue AE, Dittmer H: Multiple organ failure in poly-trauma patients. J Trauma 23:775-787, 1983.
44. Zellweger R, Ayala A, DeMaso CM, Chaudry IH: Trauma-hemorrhage causes prolonged depression in cellular immunity. Shock 4:149-153, 1995.
45. Baue AE, Gunther B, Hartl W, Ackenheil M, Heberer G: Altered hormonal activity in severely ill patients after injury or sepsis. Arch Surg 119:1125-1132, 1984.
46. Lemke DM: Riding out the storm: sympathetic storming after traumatic brain injury. J Neurosci Nurs 36:4-9, 2004.
47. Molina PE: Noradrenergic inhibition of stress-induced TNF upregulation in hemorrhagic shock. J Neuroimmunomod 9:125-133, 2001.
48. Tiegs G, Bang R, Neuhuber WL: Requirement of peptidergic sensory innervation for disease activity in murine models of immune hepatitis and protection by β-adrenergic stimulation. J Neuroimmunol 96:131-143, 1999.
49. Kees MG, Pongratz G, Kees F, Schölmerich J, Straub RH: Via β-adrenoceptors, stimulation of extrasplenic sympathetic nerve fibers inhibits lipopolysaccharide-induced TNF secretion in perfused rat spleen. J Neuroimmunol 145:77-85, 2003.
50. Yang S, Zhou M, Chaudry IH, Wang P: Norepinephrine induced TNF production in isolated liver prevented by α2 adrenergic antagonist. Biochim Biophys Acta 27:49-57, 2001.
Keywords:

Sympathetic nervous system; norepinephrine; neuroimmunomodulation; injury; stress; hemorrhage

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