Review Article | Open Access | Volume 1 | Issue 2 | 2020 | DOI No.: 10.46439/autoimmune.1.007
Role of estrogen in neuroimmunomodulation in the periphery and onset of autoimmune dysfunction
Rahul S. Nair, Hannah P. Priyanka*
Inspire Lab, Institute of Advanced Research in Health Sciences Tamil Nadu Government Multi Super Speciality Hospital, Omandurar Government Estate, Chennai-600002, India
- *Corresponding Author:
- Hannah P. Priyanka
Inspire Lab, Institute of Advanced
Research in Health Sciences Tamil Nadu
Government Multi Super Speciality
Hospital, Omandurar Government
Estate, Chennai-600002, India
E-mail:hannahpriyanka@gmail.com
Received date: September 07, 2020; Accepted date: November 20, 2020
Citation: Nair RS, Priyanka HP. Role of estrogen in neuroimmunomodulation in the periphery and onset of autoimmune dysfunction. Arch Autoimmune Dis 2020; 1(2):37-43.
Copyright: © 2020 Nair RS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Maintenance of neuroendocrine-immune homeostasis is tightly regulated by the active involvement of neural, endocrine and immune mediators. As age progresses, this bidirectional regulation losses its robustness due to the influence of several factors especially, gonadal hormones. Among the hormones, estrogen has gained significant attention due to its diverse effects as a potent modulator on the cellular and systemic level which influences both physiological and psychological functions. The mechanistic implications through which estrogenic hormones promote the onset of age-associated diseases are complex especially, its effects on the immune system which is vital for the maintenance of health. This review aims to understand the mechanisms of estrogen-mediated neuroendocrine-immune interactions to facilitate healthy aging, and extent of its effects on the onset of autoimmune dysfunction that may aid the development of better treatment strategies for auto-immune disorders.
Keywords
Estrogen; Neural-immune; Lymphoid organs; Autoimmune disorder
Introduction
Neuroendocrine-immune communication is an intricate interdependent network between the three super systems: the nervous system, the endocrine system, and the immune system. This bidirectional communication is necessary for the maintenance of homeostasis [1,2]. The trophic hormones from the pituitary are under tight regulation by the hypothalamic neuroendocrine system through the release of neurotransmitters, neuropeptides, and hormones; and modulate endocrine functions to maintain physiological homeostasis [1,3]. In turn, the immune system tightly regulates systemic functions, through release of cytokines and chemokines that can cross the blood-brain barrier [4].
Hormones play a diverse role, through its modulatory effects on the neural-immune network throughout reproductive life. Among the several hormones, estrogen has drawn a significant attention because of its pleiotropic effects on neural-immune communication. The effects of estrogen on cellular functions are influenced by receptor subtype status, dose, and duration of exposure [5,6]. Various studies have demonstrated that estrogen treatment confers neuroprotection, but in some cases, it has shown contradictory results [7]. Estrogen has shown modulatory effects on the immune system through a number of pathways and understanding the interdependence of these pathways is a necessity to appreciate the onset of the diseases. Estrogen is recognized as an important immunomodulator, showing significant effects on cellular proliferation, hematopoietic cell differentiation, and cytokine production [8-11].
In this review, we discuss the role of estrogen in influencing neural-immune interactions in the peripheral lymphoid organs (thymus, spleen and lymph nodes), and its involvement in the onset of auto-immune dysfunction contributing to the development and progression of auto-immune disorder with focus on the rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS).
Estrogen-induced Neuroimmunomodulation in the Lymphoid Organs
Several studies have established that nerve fibers such as noradrenergic (NA) and peptidergic fibers, extensively innervate the primary (bone marrow and thymus) and secondary lymphoid organs (spleen, lymph nodes, and lymphoid tissues). These nerve fibers release neural mediators to modulate immune functions. The presence of α- and β-adrenergic receptors (ARs) on T and B lymphocytes, macrophages, and other immune cells have been demonstrated and their role in immunomodulation has been studied by our lab and others [12-15]. Estrogen also modulates the immune system via its receptors, through modulation of the intracellular signalling cascade [6]. The estrogen receptors (ERs) are expressed differentially on lymphocytes with ERβ expressed predominantly on CD4+ T cells while ERβ on B cells that may be involved in maturation and differentiation of T cells in thymus and alteration of B lymphopoiesis in bone marrow [16]. Also, the presence of ERs on the natural killer (NK) and dendritic cells implicates that innate immunity is also regulated in addition to acquired immunity via NF-κB signaling mechanism [17]. Studies also showed a modulatory effect of estrogen on the activation and proliferation of lymphoid cells, thus determining the capability for cytokine and antibody production [18]. Estrogen augments the shift towards Th2 cytokine profile, thereby enhancing humoral immunity and decreasing cellmediated immunity by suppressing the proliferation of CD4+ T cells involving ERβ-associated mechanism [19].
Estrogen attenuates neuro-immune communication in thymus
Studies have established that estrogen reduces the early thymic progenitor cell population and facilitates the arrest of T cell maturation mediated by ER-β and Fas/FasL pathway that may suppress the neural-immune network [20,21]. Treatment of early middle-aged rats for 30 days with estrogen prevented age- and ovariectomy (OVX)-related increase in the tyrosine hydroxylase (TH) expression in the thymus depending on the dose of estrogen, further accompanied by differential expression of nerve growth factor (NGF) and enhanced expression of intracellular signaling molecules such as p-ERK, p-CREB, and p-Akt that may alter sympathetic NA modulation of thymopoiesis [22]. Estrogen also significantly enhanced lipid peroxidation and production of free radicals, despite an increase in the activities of anti-oxidant enzymes, providing inference that the reactive species may promote sympathetic NA degeneration in thymus and facilitating inflammatory environment [23].
Estrogen-induced neural-immune communication in spleen
Estrogen has shown diverse effects on sympathetic NA neuronal expression and immune responses in the spleen of early middle-aged rats implanted with 17β-estradiol slow release pellets (0.6 μg or 300 μg) for 30 days [24]. Of particular interest is the dose-dependent role of estrogen in modulating neural-immune interactions in the immune effector cells from the spleen. Treatment with lose dose of estrogen (0.6 μg) reduced interferon-gamma (IFN-γ) production and enhanced concanavalin A (Con A)-induced lymphoproliferation, interleukin-2 (IL-2) production, expression of intracellular signaling markers (p-ERK, p-CREB, and p-Akt), activities of anti-oxidant enzymes and nitric oxide (NO) production in the spleen [24]. Treatment with high dose of estrogen (300 μg) however, suppressed Con A- induced lymphoproliferation but increased the expression of p-TH, NGF, intracellular signaling molecules (p-ERK and p-CREB), and activities of anti-oxidant enzymes [24]. Despite these protective effects of estrogen, the production of lipid peroxidation and protein carbonyl formation were enhanced, implicating that the estrogen-mediated oxidative stress may compromise immune functions with advancing age [25]. Studies, both in vitro and in vivo, have shown similar dose-dependent effects of estrogen on splenocyte proliferation and cytokine production [6,12,13]. In vitro, treatment of splenocytes with lower dose of estrogen (10-10 M-10-12 M) enhanced the lymphoproliferation and production of IFN-γ, whereas treatment with higher doses (10-6 M-10-8 M) had no effect indicating dose-dependency [6]. Also, co-treatment of 17β-estradiol (E2) with α1- or α2-adrenergic receptor (AR) agonists and antagonists had differential effects on immune cell proliferation and intracellular signalling molecules suggesting that E2 can modulate αAR-mediated immune responses [12]. Treatment of splenocytes with estrogen and β2-AR agonist modulated β2-AR-induced immunosuppression through ERα involving cell survival (ERK, PKA and PKC) and inflammation-inducing (NF-κB and NO) pathways that may promote regulation of Th1/Th2 immunity and inflammation during aging [13].
Estrogen-induced neural-immune interactions in lymph nodes
In middle-aged OVX female rats, estrogen treatment (300 µg slow release pellets/30 days) induced significant modulation in the neural-immune network in the skin-draining (inguinal and axillary) and gut-draining (mesenteric) lymph nodes. There was a decline in the lymphocyte proliferation, IFN-γ, tumor necrosis factoralpha (TNF-α) production, and p-Akt/Total Akt expression in the inguinal and axillary lymph node of early middle-aged female rats [26]. Once again, the dose dependency of the immunomodulatory effects of estrogen on the immune effector cells from the lymph nodes is observed in this study. Contrary to the high dose estrogen treatment, low dose estrogen [0.6 µg slow release pellets/30 days] in OVX rats shown a significant increase in lymphoproliferation, IFN-γ and TNF-α, ROS production, expression of p-NF-κB (p50 and p65), p-mTOR, and p-Akt/Total Akt and decreased cytochrome C oxidase activity concomitant with in vitro findings [26]. These studies reiterate the findings that estrogen can act in a dual manner on immune effector cells and influence neural mediators based on the concentration, type of activation and duration of exposure. Another significant finding of this study was that estrogen treatment enhanced malondialdehyde (MDA) formation and NO production. Estrogen may play a role in promoting the development of inflammatory milieu in the inguinal and axillary lymph nodes through enhanced IFN-γ and TNF-α production, intracellular signaling markers such p-Akt, p-mTOR, cytochrome-c oxidase activity, and NO production aided by an increase in lipid peroxidation in the lymphocytes isolated from skin-draining lymph nodes of early middle-aged female rats [26]. In the gut-draining lymph nodes however, estrogen augmented expression of target-derived growth factor expression such as p-TH and NGF in early middle-aged female rats thereby restoring age-associated decline in compensatory mechanisms. Activity of antioxidant enzymes were also enhanced in a dosedependent manner suggesting neuroprotective effects of estrogen in the mesenteric lymph nodes (MLN) [22]. The expression of the intracellular signaling molecules (p-ERK and p-CREB) was enhanced by treatment with estrogen that may aid in truncating bacterial translocation and inflammation [27,28]. Differences in the estrogen-induced Neuroimmunomodulation in these lymph nodes may be attributed due to the differences in the functionality of the stromal cells that determines the trafficking of cells of the immune system [29].
Estrogen and Auto-immune Disorders
The differential effects of estrogen on the immune system implicate it’s involvement in the onset of autoimmune-disorders. The role of estrogen is complicated and in some disorders, estrogen has shown to be immunostimulatory while in others as inhibitory [8,9]. Estrogen-mediated effects in disease like SLE worsen during pregnancy; others including MS, RA, uveitis and thyroiditis improve, likely due to the maternal shift from a Th1 to Th2 immune response. The diseases that are critically dependent on the T cell-dependent Th1 response; benefit from this diversion, while in SLE a shift to the Th2 propagates the autoantibody response leading to worsening of the disease state [8,9,16]. Studies have shown that estrogen activates B cell function and influences T and B cell lymphopoiesis [16,21]. Reduction in thymic cellularity causing thymic atrophy is observed in treatment with high dose of estrogen [21]. The effect of estrogen on the homeostasis of the immune system is complex, and depends on the cell/tissue type, dose and duration of exposure, expression of receptor subtypes and physiological or pathological contexts [6,30].
RA
RA is the common rheumatic autoimmune disorder with a high female to male incidence both in middle and old age, thereby implicating the role of estrogen in the onset of systemic dysfunction [31-33]. The role of estrogen and its metabolites in the onset of RA is complex, as it is well-established that estrogenic hormones can both stimulate and suppress chronic inflammatory arthritis. The development of collagen-induced arthritis has been prevented with estrogen treatment in mouse models of arthritis using DBA/1LAcJ mice and Lewis rats [34]. Similarly, 2-methoxyestradiol, a naturally occurring estrogen metabolite, conferred a protective effect in murine models for collagen-induced arthritis [35].
In clinical studies, serum 17β-estradiol concentrations were significantly higher in post-menopausal women (n=13) with longstanding RA, compared to controls [36]. Also, inflammatory arthritis is severe in women compared to men (incidence and severity), as evidenced by a multinational cohort study of 6,004 patients with RA [37]. In RA patients, the estrogen concentration in the synovial fluid from knee joints was observed to be 2-2.5 times higher as compared to osteoarthritis patients [38]. In vitro studies have shown that estrogen metabolites such as 16-hydroxyestrone and 2-hydroxyestradiol stimulated the proliferation of cultured human monocytes at low and high concentrations [39]. Estrogen stimulates the intra-articular monocytes, that express both ER-α and ER-β in the knee joints of RA patients, thereby contributing to hyperplasia and synovial inflammation [39,40].
Different factors are associated with the protective vs. detrimental effects of estrogen in RA. In RA women, it has been reported that pregnancy is protective for development and progression of RA. It may be due to the presence of pregnancy steroid, estriol or regulated by excessive estrogen [41]. The expression of the ERα is found to be higher than ERβ in the synovial tissues from RA patients, and inflammation enhances receptor expression to further induce proinflammatory cytokines TNFα, IL-1β, and IL-6 by PBMCs [42].
Certain case-controlled studies have shown that oral-contraceptives prevent mild-RA disease from progressing to severe condition in women [43].
Hormone replacement has beneficial effects on postmenopausal osteoporosis in RA, without activating the underlying rheumatic disease and treatment with estradiol twice a week with norethisterone enhanced lumbar spine bone mineral density in postmenopausal RA patients [44]. Patients with high serum estradiol concentrations have improved articular index and pain index compared to controls [45]. A longer period of treatment in RA women (n=88) who undertook randomized hormone replacement plus vitamin D3 with supplemental calcium/vitamin D3 and calcium alone for 2 years; resulted in reduced erythrocyte sedimentation rate, lower disease activity score and delayed the progression of bone destruction [46]. Hormone replacement was associated with significantly higher insulin-like growth factor I and decreased soluble IL-6 receptor, but standard measures of humoral and cell-mediated immune responses were not affected [47,48]. In RA patients, the hormone replacement for a 2-year period was found to be beneficial, however patient predisposed to coronary heart disease has risk of the hormone treatment, thereby preclude long-term replacement with estrogen for the majority of postmenopausal RA patients [49-51].
Estrogen receptor modifiers and estrogen receptor ligands have in-turn drawn attention in treatment of osteoporosis and modulate RA. Treatment with raloxifene in ovariectomised mice with collageninduced arthritis has shown sustained suppression of the progression of arthritis and failure to develop new joint involvement. Despite of inflammatory condition, depriving estrogen in the treated mice has sustained bone mineral density [52]. Sex-based differences have been observed in the male and female RA patients indicating that gonadal hormones affect the disease pathogenesis differentially. Con A-induced interleukin (IL)-2 and IL-17 and p-CREB expression were elevated in peripheral blood mononuclear cells from both men and women with RA. However, IFN-γ expression was suppressed in women and p-STAT-3 expression was enhanced in men [53].
SLE
SLE is another chronic systemic autoimmune disease that affects women in childbearing condition, and it can affect any organ in the body [54,55]. Elevated serum estrogen concentration exacerbates the disease state [56]. It has been reported that estrogen accelerates the progression of disease while estrogen removal ameliorates disease in female lupus-prone mice, treated with hormone replacement and hormone deprivation regimens [57].
In animal models of SLE, treatment of ovariectomised NZB/W mice with ERβ agonist 4,4’,4’’-(4-Propyl-[1H]-pyrazole-1,3,5- triyl)trisphenol (PPT), enhanced the levels of autoantibodies and proteinuria, and the animals succumbed to the disease sooner compared to controls. ERβ agonist 2,3-bis(p-hydroxyphenyl) propionitrile (DPN) treated mice however, showed reduced antidsDNA autoantibodies. These studies show the proinflammatory role of ERα and the anti-inflammatory role of ERβ in SLE models [58]. Concomitantly studies have shown that in male and female SLE animals, the deficiency of ER-α was associated with decreased autoantibody expression, glomerulonephritis, and improved the survival rate [59]. Interestingly, improvement in ERα-deficient lupus-prone female mice were significantly high compared to male mice [60]. Treatment of ERα-deficient mice with estradiol led to increased serum Th2 cytokine profile, causing increased kidney damage and death [61].
Estrogen signaling contributes to the activation or repression of a number of immunomodulatory cytokines. In SLE, various defects were observed in the phenotype signaling, homeostasis, metabolism and function of T-cells; and estrogen was found to modulate T-cell signaling and activation [62-64]. Increased levels of potent estrone metabolites were observed in SLE patients, implying epigenetic changes via the estrogen receptors [65,66]. Peripheral blood mononuclear cells (PBMCs) express ERα and ERα transcripts and T-cells from SLE patients exhibit binding of ER proteins to the ERE sites [67]. ER expression by PBMCs from patients with SLE is altered showing increased ERα mRNA levels but reduced ERαβ transcripts [68]. In lupus, intracellular ERα and ERβ showed an enhanced variability of ER expression in T-cells compared to healthy controls, indicating a pro-inflammatory role of ERα and antiinflammatory role of ERβ in SLE patients.
Another determining factor in SLE disease pathogenesis is the imbalance between Th17 and regulatory-T cells (Tregs) [69,70]. Studies have shown that interleukin-6 (IL-6) with low dose TGF-β, influences naïve CD4+ differentiation to Th17 cells rather than Tregs, thereby inhibiting TGF-β induced Treg differentiation [71]. Combination of IL-6 with IL-1β initiates FoxP3 degradation, thus implicating Il-6 as a crucial cytokine in cellular differentiation [72]. In SLE patients, increased levels of IL-6 found in the serum and urine correlates with disease progression [73-76]. Estrogen (E2) stimulates IL-6 expression by biliary epithelial cells in mice and humans [77]. IL-6 production is controlled genetically in an age and gender dependent manner. Clinical studies have reported that IL-6 production increases with age and is a dominant cytokine in women [78]. Thus, IL-6 is a critical inflammatory cytokine, which shifts the balance from Tregs to Th17. These studies indicate that estrogen plays a critical role in immune cell differentiation and function and impacts the resultant immune responses.
MS
MS is an autoimmune disease where the myelin tissue of the CNS is under the attack of autoreactive T-cells that leads to axonal demyelination and dysfunction. The neuroprotective effects of estrogen in both human and EAE mouse model of MS, are mediated through transition of the immune response from Th1 to Th2 type and suppressing immune activation [79-82]. Significant correlation in the progesterone/17β-estradiol ratios were observed during follicular and luteal phases of the menstrual cycle in women with relapsingremitting MS using brain MRI studies [83]. The relapse rate of MS is reduced in the third trimester of pregnancy, but enhanced 3-months post-partum [79]. Treatment with estriol in non-pregnant women has showed improvement in the disease lesions, presumably due to the shift from Th1 to Th2 immune response [80]. Estrogen treatment ameliorates experimental autoimmune encephalitis, and has been shown to reduce pro-inflammatory Th1, Th17 cells, IFN-γ, IL-17, TNF, and other molecules including iNOS and MCP-1 through ER-α. Estrogen also induces anti-inflammatory cytokines IL-10 and TGF-β and promotes expansion of Tregs possibly through ER-β. Estrogen suppresses CD4 T cell expansion, increases T cell apoptosis by promoting Th1 to Th2 shift and protects grey matter from atrophy. Estrogen can exert a dual role in MS pathogenesis similar to SLE by exerting pathogenic effects through ERα and neuroprotective effects through ERβ [84]. Thus, the role of estrogen in autoimmune diseases have shown to be modulated by differential expression of estrogen receptor subtypes, levels of expression of estrogen and its metabolites and down-stream signals that may contribute to inflammatory or anti-inflammatory signals.
Conclusion
With advancing age, the estrogen plays crucial role involving diverse effects on the neural-immune network that may promote development of autoimmune diseases such as RA, SLE, MS, etc. The alterations in estrogen levels may induce modulatory effects on the neural-immune network in the peripheral lymphoid organs that leads to the development of autoimmune diseases. Through various findings, it has been observed that the estrogen behaves in a dual manner with differential effects mediating dysregulation in the neural-immune communication in peripheral lymphoid organs, in contrast to its neuroprotective property in the central nervous system. Understanding the extent of estrogenic alterations and its influence on systemic functions might provide a better insight on the role of estrogen in neuroimmunomodulation and pave the way for development of better therapeutic targets to prevent the onset of autoimmune dysfunction.
Acknowledgement
Supported by the Department of Science and Technology, Government of India, New Delhi under the Inspire Faculty Award Scheme of AORC (IFA15/LSBM-154).
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