Estrogens – Protection Rheumatoid Arthritis
Annica Andersson and colleagues from the Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden published in Arthritis Research & Therapy a study indicating that the regulation exerted by estrogens, to the Th17 cell traffic and migration, may play an important role in the well established protective role of female hormones in rheumatoid arthritis (RA).
The sexual dimorphism in autoimmune diseases is a well-known but still not fully understood phenomenon. Thus, maladies such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis and autoimmune thyroid diseases have an increased incidence and prevalence in females.
In rheumatoid arthritis, the female-to-male ratio is 3:1, with the peak RA’s incidence in women during menopause, when estrogen levels rapidly drop. Interestingly, estrogen levels are lower in postmenopausal women than in men of corresponding age.
During pregnancy, when sex hormone levels rise, up to 75% of RA patients experience relief of disease symptoms. In a well-established experimental model of RA, collagen-induced arthritis (CIA), it has repeatedly been shown that estrogen ameliorates disease development. Regarding human RA, some studies indicate that hormone replacement therapy including estradiol might be beneficial; however, the results of studies in this field are inconsistent.
In contrast to RA, estrogen aggravates systemic lupus erythematosus. Indeed, estrogen is a potent immunomodulatory agent and can exert stimulatory as well as regulatory effects on the immune system, such as enhancing B cell antibody production, reducing B and T lymphopoiesis and inhibiting T cell-dependent inflammation.
Th17 cells are major pro-inflammatory and pathogenic cells in many autoimmune and inflammatory diseases.
In RA, Th17 cell frequency and level of synovial fluid IL-17 strongly correlate with disease activity. Phase II clinical trials on RA patients receiving anti-IL-17A treatment resulted in significantly decreased disease activity scores. IL-17 augments joint inflammation by stimulating synovial fibroblasts to produce CXCL8 (IL-8), thereby attracting neutrophils to the joints.
Moreover, IL-17 plays a role in inflammation-induced bone loss by stimulating osteoclastogenesis. Migration of Th17 cells to the site of inflammation is mainly orchestrated by the interaction of C-C chemokine ligand 20 (CCL20) with C-C chemokine receptor 6 (CCR6) that is expressed on the Th17 cell.
Effects of estrogen on Th17 cells have mostly been studied in the context of experimental multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), another Th17-driven disease where estrogen is protective. Estrogen decreases production of IL-17 in EAE and inhibits Th17 differentiation and disease progression, dependent on estrogen receptor α (ERα) in T cells.
However, effects of estrogen on the Th17 cell population in arthritis have been scarcely studied, and are limited to studies on IL-17 production.
Now, the research group from Gothenburg, Sweden found that in the murine collagen-induced arthritis model, estrogen regulates traffic of Th17 cells during the development of arthritis, by increasing the migration of Th17 in early arthritis to the lymph nodes and decreasing Th17 migration to joints in established arthritis.
As estradiol increased CCR6 expression on lymph nodes’ Th17 cells and the production of CCL20, the authors suggest that the interactions within the CCR6-CCL20 pathway are responsible for the retention of Th17 cells within the lymph nodes. This may explain why the Th17 cell migration to joints is prevented, which contributes to the diminished neutrophils’ recruitment and reduced joint’s inflammation.
Of note, migration of Th17 cells to the joints in arthritis is orchestrated mainly by CCL20 and corresponding receptor CCR6 expressed on Th17 cells.
In conclusion, estrogens influence Th17 migratory pathways in arthritis, suggesting that E2 treatment might result in Th17 cell retention in LNs thus preventing migration of Th17 cells to joints.
The study increases the understanding of the role of estrogen in autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease. Thus, this study may provide new insights into mechanisms driving the sexual dimorphism in rheumatoid arthritis.
Source: Arthritis Research & Therapy
Read more: ncbi.nlm
An Update
2018
A 2018 study by Maria Luisa Dupuis et al. provides new insights regarding the anti-inflammatory effects of the phytoestrogen silibinin in T cell immunity.
Background: Silibinin, the major active constituent of silymarin extracted by the milk thistle (Silybum marianum), has been suggested to have an ERβ selective binding. Silibinin is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects; however, the role of silibinin in modulating human immune responses and its impact on autoimmunity remains unclear.
The authors of this study demonstrate that silibinin upregulates ERβ expression, induces apoptosis, inhibits proliferation, and reduces expression of the pro-inflammatory cytokines IL-17 and TNF-α, through ERβ binding, in T lymphocytes from both female and male healthy subjects. They also confirmed these results in T lymphocytes from patients with RA in term of apoptosis, proliferation, and cytokine production. Finally, they found that silibinin acts as an epigenetic modifier, down-modulating the expression of miR-155 which plays a key role in the pathogenesis of RA.
In conclusion, this in vitro study provided new insights regarding the anti-inflammatory activities of silibinin. However, in vivo assays (e.g., collagen-induced arthritis model) are needed to confirm the potential role of this compound as therapeutic tool in RA, paving the way for clinical trials in this disease.
2022
A 2022 review by Charles Raine and Ian Giles summarized the evidence that estrogens exert direct anti-inflammatory actions on T cells. Thus, silibinin, a natural agonist of estrogen receptor (ER)-β was shown to reduce the in-vitro expression of pro-inflammatory interleukin (IL)-17 and TNFα in T cells from healthy donors and patients with active RA. Silibinin has also been shown to stimulate apoptosis of human RA synoviocytes in vitro and reduce the production of inflammatory cytokines in rats with collagen-induced arthritis.
The authors of this review discussed that estrogens generally exert inhibitory effects on pro-inflammatory TH1 cells, while they may inhibit pro-inflammatory TH17 cells via ERα or have the opposite effect via ERβ. At high concentrations such as seen in pregnancy, estrogens induce the secretion of IL-10 and suppress TNFα production in T cells, supporting an anti-inflammatory cytokine milieu.
Moreover, according to the authors, it has been shown that estrogen treatment before immunization with collagen can retard disease development in collagen-induced arthritis (CIA), a mouse model of RA.
And, also, estradiol has been linked to expansion of anti-inflammatory Treg cells in pregnant mice with autoimmune encephalitis and pregnancy-induced amelioration of joint inflammation has been achieved by treatment of non-pregnant SKG mice (a model of human RA) with either estradiol or progesterone at pregnancy-like levels.
2023
In a 2023 Editorial Maurizio Cutolo and Emanuele Gotelli discussed the complex role of estrogens in the risk and severity of rheumatoid arthritis in menopause.
The authors of this editorial discussed that estrogens exert both complex proinflammatory and anti-inflammatory effects that may differ depending on the cell type mainly involved in the specific autoimmune disease onset and progression (i.e., T or B cells) and on the doses or concentrations involved (exogenous and/or endogenous sources).
They pointed out that estrogens exert proinflammatory effects on B cells and anti-inflammatory effects on T cells, especially at high concentrations, by inhibiting T helper 1 (TH1) cells, TH17 cells via estrogen receptor-α and on macrophages. Additionally, the authors discussed that estrogens seem to support regulatory T cells and TH2 cell-associated cytokines production (interleukin (IL)-4, IL-10 and transforming growth factor-β).
Furthermore, the authors stated that pregnancy and its related increase of estrogen levels are commonly considered protective elements against disease flares in patients with RA, as shown by a lower disease activity at the beginning of pregnancy. On the other hand, post-partum and breast feeding are linked to disease flares in almost all rheumatic diseases, including RA. Equally, menopause is often linked to the worsening of ongoing rheumatic disease outcomes, observed also in RA, which is related to the dramatic decrease in gonadal steroids production, especially estrogens, that occurs during this phase.
Cover Image Credits: (Left panel): E2 cell receptors in different cell populations: different effects of estrogen concentrations upon estrogen receptors ER-α and ER-β present on each cell. Left: receptors and cells were they are present. Horizontal red arrow: gradient of estrogen concentrations. Blue arrows: decrease of an effect by estrogen concentration. Red arrows: increase of an effect by estrogen concentrations. From: ‘The Role of Estrogens in Rheumatoid Arthritis Physiopathology’, by Maria Fernanda Romo-García et al., From the Edited Volume Rheumatoid Arthritis – Other Perspectives towards a Better Practice, Published: 27 August 2020, DOI: 10.5772/intechopen.93371
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