Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases—The 10-year update
Introduction
In the larger universe of Behavioral and Biopsychosocial Research, neuroendocrine immune pathways can be viewed as the hardware connections between the CNS and periphery. In 2001, research on neuroendocrine immunology in rheumatic diseases was reviewed [1]. This present review updates knowledge on the involvement of endocrine axes and peripheral nervous systems in chronic inflammatory diseases (CIDs). We do not touch non-inflammatory fibromyalgia or stress-related aspects of rheumatic diseases because these subjects are demonstrated elsewhere in extensive form [2], [3]. Since the 1990s, knowledge increase in the field of neuroendocrine immunology of the rheumatic diseases entered an exponential phase. Thus, we are not able to review all advances in the field. Only conclusive aspects of neuroendocrine immunology research in CIDs are summarized.
Section snippets
The female to male preponderance in rheumatic diseases—the role of sex hormones in autoimmunity
Sex discrepancy is a long-recognized factor in CIDs with a higher proportion of female than male patients affected [4]. While the anti-inflammatory role of androgens is accepted, recent evidence suggests that estrogens can have both pro- and anti-inflammatory activities [5]. Estrogens can accelerate immune complex glomerulonephritis, but ameliorate T cell-mediated focal sialadenitis, renal vasculitis, and periarticular inflammation in the same autoimmune model [6]. In models, estrogens can
Deficiency of adrenal and gonadal androgens in rheumatic diseases
Serum levels of anti-inflammatory androgens are mainly low in active human CIDs due to a cytokine-induced block of androgen production in the adrenal and gonadal glands (Fig. 2) [9] and owing to increased conversion of adrenal androgens to downstream estrogens in inflamed tissue (androgen drain) (Fig. 2). The role of sex hormone-binding globulin has not been studied in detail but might have an impact on the results [10]. Of note, adrenal androgens can be relatively increased in very acute forms
Increased conversion of androgens to estrogens—the androgen drain
In inflamed tissue and inflammatory cells of patients with CIDs, androgen precursors demonstrate increased conversion to downstream estrogens (independent of biological sex) [13]. In immune cells, it can be observed by directly studying androgen-to-estrogen conversion (Fig. 2) [14]. The proinflammatory cytokine TNF is able to activate the aromatase and androgen-into-estrogen conversion in peripheral cells (Fig. 2) (reviewed in [15]). TNF blocks the activation of biologically inactive androgen
Disturbances of the hypothalamic–pituitary–gonadal (HPG) axis
The first experimental evidence that proinflammatory cytokines can interfere with the global function of the HPG axis came from IL-1β studies in rodents [20]. Similarly, HPG axis abnormalities were observed in human studies of male RA patients, reflected as elevated follicle-stimulating hormone and luteinizing hormone levels, compared to controls [21]. This finding was observed in male patients with ankylosing spondylitis and SLE [22], [23], and in patients with Sjögren syndrome, when
Dehydroepiandrosterone sulfate levels and the risk of developing an autoimmune disease
The adrenal hormone DHEAS is an important precursor of peripheral anti-inflammatory androgens and low levels have been considered a susceptibility biomarker in studies of RA in premenopausal onset women [30]. Two other investigations in patients with RA did not confirm the earlier findings, but used different assay methods [31], [32]. Production capacity of the adrenal glands might be better studied using functional tests (CRH test, ACTH test, or circadian rhythms of hormones). The theory of
Inadequate secretion of ACTH and cortisol relative to inflammation—the disproportion principle
Basal blood levels of ACTH and cortisol are not much different in human CIDs compared to healthy controls (summarized in [34]). Upon subtle stimulation of the HPA axis using stress tests or mild exercise, however, one can observe decreased activity of the HPA axis in RA patients [35], [36]. Considering an increased proinflammatory status in these patients, the HPA axis response is relatively inadequate (lower than expected from acute inflammatory stimulation) (Fig. 3).
Single cytokines, such as
The link between cytokines and hormonal abnormalities—effects of biologics on hormonal axes
In RA patients, TNF and IL-6 neutralizing therapies consistently increase adrenal androgens relative to cortisol or precursor hormones of androgens [41], [42], [43], [44]. Although the cytokine-neutralizing effects may seem to be small, the ratio of androgens to precursors increased by a relative factor of 2–3 over 12 weeks, which is a sign of normalization of the human HPA axis and, thus, steroidogenesis [41], [42]. Another study in RA patients demonstrated that TNF neutralization is
Corticotropin-releasing hormone in local inflammation
The proinflammatory role of local corticotropin releasing hormone (CRH) and its presence in synovial fluid of patients with RA is known [46]. In 2001, CRH mRNA was found upregulated in the synovial tissue of patients with CIDs, but not in normal synovial tissue [47]. Inflammatory cytokines enhance the transcriptional activity of the human CRH promoter in primary synoviocytes. In addition, the CRH antagonist antalarmin ameliorated experimental arthritis [48]. In conclusion, although central CRH
Alpha melanocyte-stimulating hormone (α-MSH) in inflammation
The anti-inflammatory role of α-MSH has been described for two decades in animal models of irritant and allergic contact dermatitis, vasculitis, and fibrosis, ocular, gastrointestinal, brain, and allergic airway inflammation, and arthritis [49], [50]. Until now, no suitable derivatives of α-MSH have been tested in patients with CIDs, although the anti-inflammatory effect in animal models is well known.
Prolactin in rheumatic diseases
In human CIDs, serum levels of proinflammatory prolactin were found to be normal or slightly elevated [51], [52]. The PRL-1149G/T polymorphism (rs1341239) in the prolactin gene decreases prolactin expression, and this was associated with a decreased risk to develop RA [53]. Prolactin has many immunostimulatory (T helper type 1 favoring) and proinflammatory activities [54]. Thus, some small therapy studies tested pituitary inhibition of prolactin secretion by bromocriptine in which some patients
Melatonin in rheumatic diseases
The nocturnal pineal hormone melatonin has been linked to human chronic inflammation. At normal to slightly elevated serum concentrations, it stimulates many aspects of the immune/inflammatory response [55]. Treatment of RA patients with melatonin is associated with worsening of the inflammatory condition [56]. The immune-supportive role of melatonin has been implicated in the context of circadian rhythms of the immune/inflammatory reaction and clinical symptoms in humans. In RA, melatonin
The hypothalamic–pituitary–thyroid axis in rheumatic diseases
The role of thyroid hormones as stimulators or inhibitors of inflammatory pathways is not clear. A link between inflammation and lowered thyroid hormones was found in non-thyroidal illness syndrome (NTIS) in humans. This condition is a consequence of injury, inflammation, or starvation having the following characteristic changes [59]:
- (1)
downregulation of hypothalamic TRH,
- (2)
lowered secretion of thyroid-stimulating hormone (TSH), free T4 (thyroxin), and free T3 (triiodothyronine),
- (3)
decreased levels of
Circadian rhythms of hormones and cytokines: The lesson from rheumatoid arthritis
In a recent review, the circadian rhythm of RA symptoms was demonstrated with typical early morning increase of stiffness, functional disability, pain, and other features [62]. These increased manifestations are a consequence of the nightly increase of proinflammatory cytokines, such as IL-6, TNF, and others, in patients with CIDs [63]. The increase of TNF and IL-6 stimulates the morning rise of endogenous ACTH, cortisol, adrenaline, and noradrenaline, showing a lag phase of 30–60 min between
The role of the sympathetic nervous system (SNS)
The influence and role of the SNS in inflammation depends mainly on 7 major conditions (Table 1). Thus, no simple answer can be given to the question, “What is the role of the SNS in CIDs?” In order to understand the influence of the SNS, it is helpful to separate three phases of inflammation (acute = the first 12 h; intermediate = 12 h to 4–6 weeks; and chronic = equal 6 or more weeks). This review briefly recapitulates important SNS aspects of the three phases. The interested reader is referred
Vasoactive intestinal peptide
Vasoactive intestinal peptide (VIP) has many similarities to noradrenaline (via the β2-adrenoceptor and cyclic AMP), because it switches on similar intracellular cascades [89]. Although VIP has been known since the late 1960s, its strong anti-inflammatory role in animal models of CIDs was discovered during the last decade [89]. No VIP-related therapies are currently on the market, but non-peptide agonists to VIP receptor type 1 and 2 are developed for therapy testing in experimental and human
The cholinergic pathway
In 2001, this anti-inflammatory pathway was not appreciated. The parasympathetic nervous system has great complexity of nicotinergic and muscarinic receptors that induced resistance to research in the scientific community (4 subfamilies of nicotinic receptors with 17 different subunits, and 5 muscarinic G protein-coupled receptors). With the discovery of an acute anti-inflammatory effect of vagus nerve electrical stimulation in an acute experimental model of endotoxin-triggered systemic
The sensory nervous system and pain pathways
In 2001, the proinflammatory role of substance P, the mechanisms of peripheral and central sensitization, and sensory hyperinnervation of inflamed tissue were known features in humans and rodents [1], [94]. The main discovery in this field was the understanding that proinflammatory cytokines from glial cells support spinal sensitization in rodent models [95]. This finding is demonstrated in experimental models of arthritis by intrathecal neutralization of TNF, which has a strong influence on
Neuroendocrine immune modulation of the IL-17/Th17 and Treg pathway
While at the beginning of the decade the concept of CD4-positive T helper type 1 and T helper type 2 was in the focus, the last decade added the important IL-17A-dependent T helper type 17 pathway and T regulatory cells (earlier called suppressor T cells). Effects of hormonal and neurotransmitter/neuropeptide influence on these cells are demonstrated in Table 2. The picture for Th17 modulation is not always clear-cut which might depend on the way of IL-17 induction. IL-17 is induced by IL-6 and
Evolutionary medicine, energy regulation, and neuroendocrine immunology
While in 2001, we reviewed a possible pathophysiological influence of neuroendocrine pathways on the disease process in CIDs [1], neuroendocrine immune alterations and other disease sequelae were unexplained. In the last decade, a theory was formulated, which links elements of neuroendocrine regulation, chronic immune stimulation, evolutionary medicine, energy homeostasis, and water/volume regulation. The theory helps to explain systemic disease sequelae of CIDs. The theory is briefly
Four major lines of rational neuroendocrine immune therapy
In the last decade, four lines of rational neuroendocrine immune therapy were established in the clinic. First, adrenal androgens such as DHEA have mild anti-inflammatory effects in SLE [116], [117], and Sjogren syndrome [118], but not in RA or for fatigue in CIDs [119], [120], [121]. Overall, effects of this androgen are mild, which might depend on conversion to anti- but also proinflammatory downstream hormones depending on the situation in inflamed tissue (see above).
Second, low-dose
Conclusions
The last 10 years demonstrated many new aspects of neuroendocrine immune mechanisms in rheumatic diseases, which support an important immunomodulating role of hormones and neurotransmitters of the nervous system.
A new theory encompassed many neuroendocrine abnormalities on the basis of evolutionary medicine, energy regulation, and volume regulation. Sequelae of CIDs are interpreted as a long-term neuroendocrine re-allocation program of energy-rich substrates to an activated immune system on a
References (197)
- et al.
Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice 86
Cell Immunol
(1992) - et al.
The relationship between endogenous testosterone, preandrogens, and sex hormone binding globulin and knee joint structure in women at midlife
Semin Arthritis Rheum
(2007) - et al.
Influence of CYB5A gene variants on risk of rheumatoid arthritis and local endocrine function in the joint
Brain Behav Immun
(2013) - et al.
Roles of prolactin and gonadotropin-releasing hormone in rheumatic diseases
Rheum Dis Clin North Am
(2000) - et al.
Prolactin in autoimmunity and antitumor defence
J Neuroimmunol
(2000) - et al.
Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial
Lancet
(2008) - et al.
Uncoupling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis in inflammatory bowel disease?
J Neuroimmunol
(2002) - et al.
Functional alpha 1-adrenergic receptors on leukocytes of patients with polyarticular juvenile rheumatoid arthritis
J Neuroimmunol
(1996) - et al.
Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPS-I)
J Pain
(2009) - et al.
Involvement of the hypothalamic–pituitary–adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role
Arthritis Rheum
(2001)