Abstract
IntroductionThe incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis.MethodsOvariectomized DBA/1 mice treated with 17β-estradiol (E2) or placebo were subjected to collagen-induced arthritis (CIA), and arthritis development was assessed. Th17 cells in joints and lymph nodes were studied by flow cytometry. Lymph node Th17 cells were also examined in ovariectomized estrogen receptor α–knockout mice (ERα−/−) and wild-type littermates, treated with E2 or placebo and subjected to antigen-induced arthritis.ResultsE2-treated mice with established CIA showed reduced severity of arthritis and fewer Th17 cells in joints compared with controls. Interestingly, E2-treated mice displayed increased Th17 cells in lymph nodes during the early phase of the disease, dependent on ERα. E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes.ConclusionsThis is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis. We report that E2 treatment results in an increase of Th17 cells in lymph nodes during the early phase of arthritis development, but leads to a decrease of Th17 in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 pathway, which is important for Th17 cell migration. This study contributes to the understanding of the role of estrogen in the development of autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0548-y) contains supplementary material, which is available to authorized users.
Highlights
The incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones
E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node T helper 17 cells (Th17) cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes
This is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis
Summary
The incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, in rheumatoid arthritis. The peak incidence of RA in women coincides with the time of menopause, when estrogen levels rapidly drop, connecting sex hormones to disease etiology [1]. During pregnancy, when sex hormone levels rise, up to 75% of RA patients experience relief of Andersson et al Arthritis Research & Therapy (2015) 17:32 production, reducing B and T lymphopoiesis and inhibiting T cell-dependent inflammation [9,10,11,12]. The cytokine interleukin (IL)-17A (referred to as IL-17) is produced mainly by T helper 17 cells (Th17) and constitutes the driving force in several autoimmune diseases. 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 [19]
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