Currently, it is generally accepted that multiple sclerosis (MS) is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses that lead to damage of myelin. In this respect, intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress as well as a variety of other lifestyle interventions can influence the neuroendocrine system. On its turn, it has been demonstrated that the neuroendocrine system has immunomodulatory potential. Moreover, the neuroendocrine and immune systems communicate bidirectionally via shared receptors and shared messenger molecules, variously called hormones, neurotransmitters, or cytokines. Discrepancies at any level can therefore lead to changes in susceptibility and to severity of several autoimmune and inflammatory diseases. Here we provide an overview of the complex system of crosstalk between the neuroendocrine and immune system as well as reported dysfunctions involved in the pathogenesis of autoimmunity, including MS. Finally, possible strategies to intervene with the neuroendocrine-immune system for MS patient management will be discussed. Ultimately, a better understanding of the interactions between the neuroendocrine system and the immune system can open up new therapeutic approaches for the treatment of MS as well as other autoimmune diseases.
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). It is characterized by inflammation, demyelination, axonal degeneration, and gliosis. MS affects 1 out of 1000 people in the Western world and leads to chronic disability in mostly young adults (20–40 years). This neurodegenerative disease is characterized by a heterogeneous clinical course with motor sensory and sensible disturbances [
Although MS is considered to be a predominantly immune-mediated demyelinating disease, as demonstrated by immune cell infiltration and accompanying inflammatory processes leading to damage of myelin, the etiology of MS is unknown. It is now generally accepted that MS is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses [
The neuroendocrine system is based on interactions between the nervous and the endocrine system. Furthermore, the neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. In turn, the immune system can collaborate in the regulation of endocrine activity. The bidirectional interactions between aforementioned systems are known as the neuroendocrine-immune system. The integration between these two systems is essential in order to maintain homeostasis and health. Neuroendocrine regulation of immune responses is important for survival during both physiological and mental stress. Systemically, this regulation is accomplished by hormones, such as those from the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis. Regional regulation is accomplished by innervations, including the autonomic nervous system, while local regulation is accomplished by neurotransmitters [
In a healthy individual, the neuroendocrine and the immune system provide a finely tuned regulatory system. Disturbances of these regulatory systems could potentially lead to oversuppression of the immune system for example, resulting in a higher susceptibility to cancer and infectious diseases, or overactivation of the immune system which on its turn may lead to a higher risk for inflammatory or autoimmune diseases.
In order to survive, organisms maintain a complex dynamic equilibrium or homeostasis which is constantly challenged by intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress. For several decades, it has been known that the hormonal stress response is mainly coordinated by the HPA axis. The HPA axis is a regulatory system, including the hypothalamus, pituitary, and adrenal glands and regulatory neural inputs, which functions on both a neuronal and an endocrine level through the release of neural factors and hormones. It has central and peripheral actions, mediates the coordination of circadian events such as the sleep/wake cycle, and helps with coping, adaptation, and recovery from stress.
During various physical and psychological stimuli, the HPA axis is activated which results in secretion of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of the hypothalamus into the hypophyseal portal blood supply. CRH acts on the anterior pituitary gland to stimulate the release of adrenocorticotropic hormone (ACTH). Subsequently, ACTH circulates through the systemic circulation towards the adrenal cortex where it induces the expression and release of glucocorticoids (GC) in a diurnal pattern (Figure
The neuroendocrine-immune system. Via a complex system of common messenger molecules and receptors, the neuroendocrine and the immune systems bidirectionally communicate and monitor each other’s activities. Integration of these signals is essential to maintain homeostasis and health and may result in immunosuppression or immunostimulation. Discrepancies at any level can lead to changes in susceptibility to and severity of several autoimmune and inflammatory diseases.
It is known that GC, which are amongst the best-characterized hormones, exert a wide variety of immunomodulatory effects, including modulation of cytokine expression, cell adhesion and migration, and production of inflammatory mediators [
A well-known GC is cortisol, often referred to as the stress hormone and a powerful natural immunosuppressor. Following binding to glucocorticoid receptors, cortisol is involved in several regulatory functions such as glucose metabolism, regulation of blood pressure, insulin release for blood sugar maintenance, immune function, and inflammatory responses. For example, studies have shown that cortisol can prevent T cell proliferation by downregulation of the IL-2 receptor [
Clinical and experimental studies have demonstrated that abnormalities in the HPA axis in MS may contribute to enhanced susceptibility to disease and to more severe disease activity [
Altogether, the HPA axis hyperactivity in MS has been accompanied with progressive disease and global neurodegeneration [
Besides the release of GC including cortisol, the HPA axis also regulates the secretion of prolactin and growth hormone (GH). Accordingly, these hormones exhibit immunoregulatory effects. Briefly, through stimulation by suckling and stress, prolactin is released from the anterior pituitary gland and stimulates mammary growth and differentiation. Moreover, it is documented that prolactin has immunostimulatory effects such as increasing the production of IFN-
In addition to the HPA axis, other central hormonal systems, such as the HPG axis, modulate the immune system [
The integrating center of this reproductive hormonal axis is the hypothalamus. Gonadotropin-releasing hormone (GnRH) is synthesized and released by the hypothalamus into the hypophyseal-portal circulation. Upon transport to the pituitary gland, GnRH stimulates the synthesis and secretion of gonadotropic hormones including follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which following systemic release circulate towards the reproductive organs and subsequently stimulate the release of estrogen and progesterone.
Estrogen is a potent steroid with pleiotropic effects and is present in high levels in females from adolescence to menopause. There are 3 naturally occurring estrogens: estrone (E1), estradiol (E2), and estriol (E3) which are the predominant forms during menopause, in non-pregnant females, and during late pregnancy, respectively. Estriol has been accepted as the safest of the three and has been used worldwide for the treatment of menopausal symptoms [
Furthermore, pregnancy, postpartum period, and menopause as well as other physiological conditions have been demonstrated to affect the clinical course of a variety of autoimmune disorders. These clinical observations suggest the importance of sex hormones in immune modulation. Several studies have documented that, during pregnancy, both clinical symptoms and relapse rate of MS are decreased, whereas the postpartum period is associated with a higher risk for exacerbation of the disease [
Sex differences have also been observed in EAE. Female mice are more susceptible to EAE than males, albeit that a genetic background may also influence the effects of sex hormones on the immune system [
In summary, the numerous immunomodulatory and neuroprotective effects of estrogens can attribute to their protection in several neurodegenerative and autoimmune diseases. Next to estrogens, other hormones released through the HPG axis exert immunoregulatory effects. Briefly, high levels of prolactin have been described in MS patients [
Regional regulation of the immune system through the autonomic nervous system is mediated by innervations of primary and secondary lymphoid organs. Furthermore, T cells, B cells, and DC are located adjacent to nerve terminals. Depending on the pathological conditions, innervation of lymphoid organs can change. For example, the number of innervations in lymphoid organs increases under psychosocial stress in primates, whereas it decreases following viral infection [
(1)
Several studies have indicated the involvement of catecholamines in the pathogenesis of MS, as demonstrated by increased
Dopamine, another catecholaminergic neurotransmitter, also has important functions in the peripheral nervous system, as indicated by its release from peripheral nerve endings innervating lymphoid organs as well as from immune cells. Dopamine receptors are classified into two subgroups, dopamine-1 (D1)-like receptors (D1R and D5R) and D2-like receptors (D2R, D3R and D4R) [
Similar to noradrenalin, dopamine levels are decreased in autoimmunity [
(2)
First, direct stimulation of paraganglia cells by inflammatory cytokines, such as IL-1, results in signaling through afferent fibers. This leads to activation of parasympathetic brainstem regions to release ACh from efferent vagus nerves, thereby controlling inflammation through negative feedback. Subsequent binding of ACh to nicotinic receptors blocks the NF-
The second mechanism is indirect. When the peripheral cytokine-mediated inflammatory reaction stimulates the afferent sensory vagal route, a reflex response through the HPA axis that releases ACTH and GC is activated, which in turn reduces the production of pro-inflammatory cytokines.
A major region of cholinergic input, which plays an important role in learning and memory function, consists in the basal forebrain in the hippocampus [
Local regulation of the immune system is mediated by neurotransmitters which are synthesized in neurons and act on the postsynaptic neurons and other organs. Neurotransmitters are released from both the CNS and the peripheral nervous system as well as from immune cells including T cells, B cells, macrophages, DC, and granulocytes [
(1)
Recent studies have identified glutamate as an important determinant of neurodegenerative damage in the course of MS [
Besides, mGluR are also likely to contribute to glutamate transmission changes in MS and EAE. Indeed, it has been reported that mGlu1R expression in the cerebellum of MS patients and of mice with EAE is lower in comparison with controls, while the expression of mGlu5R is increased [
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The NK-2 receptor exhibits the highest affinity for neurokinin A. Neurokinin A is known to control various vital responses in humans, such as airway contraction, vasodilatation, and vascular permeability [
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Initial evidence for involvement of serotonin in autoimmunity comes from the experimental autoimmune neuritis (EAN) model. It was shown that blockade of the serotonin transporter by a selective serotonin reuptake inhibitor, thereby increasing the extracellular levels of serotonin, suppressed EAN [
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Upon histamine 1 receptor (H1R) ligation, histamine induces an increment of the secretion of the pro-inflammatory cytokines IL-1
Already in 1983, it was noted that histamine may be involved in MS, as evidenced by 60% higher histamine levels observed in MS patients as compared to healthy controls [
Although H1R and H2R have a clear pro-inflammatory role and disease-promoting effect, H1R and H2R activation may also play an important role in limiting autoimmune responses [
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Loss of GABAergic innervations is a physiologic hallmark of MS and EAE. Additionally, it was shown that GABA is decreased in the serum and CSF of MS patients and in EAE [
Given the bidirectional interactions of the neuroendocrine and the immune systems, the immune system also regulates the neuroendocrine system through the secretion of cytokines. Cytokines are immune mediators produced in response to antigens and toxins or after stimulation by other cytokines. Cytokines and their receptors are expressed in the neuroendocrine system and exert their effects both centrally and peripherally [
Excessive pro-inflammatory cytokine production is physiologically joined to a simultaneous increment of the synthesis of anti-inflammatory cytokines, inhibitory neurotransmitters, and GC. The resulting equilibrium is called homeostasis. However, prolonged increased HPA axis activity results in a prompt loss of the anti-inflammatory mediators with an increase of pro-inflammatory mediators [
Whereas interferons were the first cytokines shown to exert neuroendocrine effects as demonstrated by increased steroid production upon interferon treatment, it is now clear that several cytokines have functions in the neuroendocrine system. Indeed, IL-1, IL-2, IL-6, IL-10, IFN-
Activation of innate immune responses, by pathogens as well as by damage-associated molecules, leads to the release of inflammatory cytokines that signal the CNS via the subdiaphragmatic vagus nerve, thereby resulting in changes that are associated with sickness behavior, such as fever [
Several cytokines are also involved in the regulation of sleep and wakefulness [
Chemokines, a large group of proteins from the cytokine family that are pivotal in leukocyte migration, were found to play a role in signaling functions in the CNS [
The aforementioned hormones, neurotransmitters, and cytokines with their immunomodulatory activity are summarized in Table
Neuroendocrine factors and their immunomodulatory effects.
Substance | Receptor | Effect on immune response | Reference |
---|---|---|---|
Acetylcholine | Muscarinic acetylcholine receptor (mAChR) | Differentiating towards a Th1 phenotype | [ |
Nicotinic acetylcholine receptor (nAChR) | Inhibits IL-1 |
[ | |
| |||
ACTH | ACTH receptor | Inhibits IFN- |
[ |
| |||
Adrenalin/ |
|
Upregulation of cAMP; inhibits IL-1, IL-6, IL-12, and TNF- |
[ |
|
Downregulation of cAMP | [ | |
| |||
Cortisol | Glucocorticoid receptor (GR) | Inhibits IFN- |
[ |
| |||
CRH | Corticotropin-releasing hormone receptor | Activates macrophages |
[ |
| |||
Dopamine | D1-like receptors | Upregulation of cAMP | [ |
D2-like receptors | Downregulation of cAMP | [ | |
| |||
GABA | GABA receptors | Reduces the proliferative response of activated CD8+ T cells |
[ |
| |||
Glutamate | mGluR1 | Enhances IL-2, IL-6, IL-10, TNF- |
[ |
mGluR5 | Inhibits IL-6 production | [ | |
| |||
Growth hormone | Growth hormone receptor | Activates macrophages and enhances H2O2 production | [ |
| |||
Gonadotropin-releasing hormone | Gonadotropin-releasing hormone receptor | Increases IL2R expression, T- and B-cell proliferation, and serum Ig | [ |
| |||
Histamine | Histamine 1 receptor, histamine 4 receptor | Enhances IL-1 |
[ |
Histamine 2 receptor | Inhibits IL-12, IFN- |
[ | |
| |||
Luteinizing hormone | Luteinizing hormone/choriogonadotropin receptor | Enhances IL-2 stimulated T-cell proliferation | [ |
| |||
Melatonin | Melatonin receptor | Enhances IL-1, IL-2, IL-6, and IFN- |
[ |
| |||
Neurokinin A | Neurokinin 2 receptor (NK2-receptor) | Enhances mRNA expression of IFN- |
[ |
| |||
Estrogen | Estrogen receptor | Enhances T-cell proliferation and activity IFN- |
[ |
| |||
Progesterone | Progesterone receptor | Enhances IL-4 production and CD30 expression | [ |
| |||
Prolactin | Prolactin receptor | Enhances T cell proliferation, IFN- |
[ |
| |||
Serotonin | Serotonin-1a receptor | Enhances NK cell cytotoxicity |
[ |
Serotonin-2a receptor | Inhibits lymphocyte proliferation | [ | |
| |||
Substance P | Neurokinin 1 receptor (NK1-receptor) | Enhances IL-1 |
[ |
| |||
Vasopressin | Vasopressin receptor | Enhances IFN- |
[ |
| |||
VIP | Vasoactive intestinal peptide receptor | Inhibits T-cell proliferation and IL-12 |
[ |
To date, none of the available therapies for MS are curative. Their primary aims are inducing remission after relapse, reducing the number of new relapses, and preventing or slowing the progression of disability. During acute relapse, patients may be hospitalized and symptomatically treated with high doses of corticosteroids. Additionally, a number of disease-modifying treatments have been approved, albeit mostly only for RR-MS. These include IFN-
Since the 1950s, GC are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, RA, MS, and other autoimmune diseases. Despite the introduction of disease-modifying therapies, GC therapy remains the first-line treatment upon relapse for inducing remission in MS sooner and with fewer deficits for the patient. Methylprednisolone is among the most commonly used corticosteroids in MS and reduces the number of gadolinium-enhancing lesions during MS exacerbations [
Although the majority of patients with MS benefits from GC treatment, a small set of patients fails to adequately respond, suggesting differences in sensitivity to GC, a phenomenon recognized as GC resistance [
Because of the aforementioned effects of circadian rhythms on the symptoms of autoimmune and inflammatory diseases, there is a growing interest in the efficacy of timed treatment or so-called chronotherapy. Although the impact of chronotherapeutics on treatment success remains to be fully elucidated, beneficial effects of chronotherapeutics have been identified in the management of MS and RA [
Different lifestyle interventions can influence the neuroendocrine-immune system, including physical exercise. Physical exercise triggers a systematic series of neuroendocrine and immune events directed at accommodating the human body to the increase in physiological demands. Furthermore, the neuroendocrine-immune system can adapt to chronic overload or exercise training. Because of the vital role of the neuroendocrine system at maintaining homeostatic control during exercise, one exercise bout results in an increase of hormonal levels, including growth hormone, testosterone, cortisol, ACTH, adrenalin, noradrenalin, and estradiol [
Aforementioned observations triggered the interest to use physical exercise in MS patients in order to manage disease-related impairments. It was shown that physical exercise beneficially affects quality of life, symptoms including depression, fatigue, and possibly cognitive functions in MS patients [
To date, the mechanisms linking physical exercise and disease status in MS patients remain, however, to be elucidated [
Several studies in EAE have shown the inhibitory effects of estrogens on disease pathogenesis [
In a first pilot crossover trial, 6 female RR-MS patients were treated with 8 mg estriol per day during 6 months, followed by a 6-month posttreatment period and a subsequent retreatment period during 4 months. The investigators reported reduced number and volume of gadolinium-enhancing lesions upon estriol treatment [
For completeness, also the effect of testosterone was evaluated in a first pilot study including 10 men with RR-MS. A daily treatment with 10 g of a 100 mg testosterone-containing gel for 12 months resulted in improvement of cognitive performance and delayed progression of brain atrophy. These findings suggest that testosterone treatment is safe and well-tolerated and may have neuroprotective effects in men with RR-MS [
(1)
(2)
(3)
(4)
(5)
In 1993, interferon (IFN)-
In addition, targeting cytokine production has been intensively investigated as a potential treatment strategy in autoimmunity [
Although knowledge of the immunopathogenesis as well as genetic predisposition of MS has greatly increased over the last decades, potential environmental triggers such as stress and pregnancy may not be underestimated in order to better understand how these factors modulate disease. In this perspective, it is clear that the neuroendocrine-immune system has an important role in the pathogenesis of autoimmune diseases, including MS. Here we have provided an overview of the complex system of crosstalk between the neuroendocrine and immune system, whereby they share an extensive range of common messenger molecules and receptors and whereby they can monitor each other’s activities. Discrepancies at any level can lead to changes in susceptibility to and to severity of several autoimmune and inflammatory diseases. These principles are now being used to test novel therapies for MS based on addressing and correcting the dysregulation of these neural and neuroendocrine pathways.
However, the key question that remains unanswered is whether these alterations in neuroendocrine pathways and receptors are involved in the pathogenesis of MS as a predisposing factor or whether they are a result of the inflammatory status of the disease. Based on preliminary evidence that hormonal changes may appear before the symptomatic phase of the disease [
In conclusion, dysfunction of the neuroendocrine-immune system in patients with autoimmune diseases, including MS, seems to be important in the pathogenesis of these diseases. Increasing the knowledge of the neuroendocrine-immune system in MS can help to elucidate the underlying mechanisms of the inflammatory responses in MS and mutatis mutandis in other autoimmune diseases. Furthermore, intensive research on the modulatory function of the neuroendocrine-immune system may provide new therapeutic approaches for the treatment of MS in the near future.
Nathalie Deckx and Wai-Ping Lee contributed equally and are the co-first authors.
This work was supported by Grant no. G.0168.09 of the Fund for Scientific Research-Flanders, Belgium (FWO-Vlaanderen), the grants of the University of Antwerp through the Special Research Fund (BOF), Medical Legacy Fund, and the Methusalem funding program, a grant of the Hercules Foundation, Belgium, and grants of the Charcot Foundation, Belgium, and of the “Belgische Stichting Roeping,” Belgium. Wai-Ping Lee holds a Ph.D. fellowship of the Flemish Institute for Science and Technology (IWT). Nathalie Cools is a Postdoctoral Fellow of the Fund for Scientific Research (FWO), Flanders, Belgium.