Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis

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.

IL-17-producing γδT cells are regulated by estrogen during development of experimental arthritis

“…All experiments started with OVX of 8-10 weeks old mice, under isoflurane-induced anesthesia (Baxter Healthcare Corporation Chicago, Illinois, USA), as described previously [27]. Mice were allowed to recover from OVX during approximately two weeks before arthritis protocols were initiated.…”

“…The mechanisms underlying estrogenmediated inhibition of arthritis are still not fully elucidated; however, we recently reported that E2 regulates Th17 cell localization during development of CIA. In that study, E2 increased levels of Th17 cells in lymph nodes but decreased Th17 cells in joints [27]. Since IL-17 is abundantly produced also by γδT cells, the aim of this study was to investigate the effects of E2 on IL-17-producing γδT cells, using different experimental models of arthritis.…”

“…Furthermore, women with RA often experience improved joint disease symptoms during pregnancy (afflicted with high levels of estrogens), and estradiol-containing hormone replacement therapy (HRT) given to postmenopausal RA patients improved joint disease activity in some studies but not in others [20][21][22][23]. Nevertheless, treatment with estrogens dramatically inhibits arthritis in various animal models of RA; antigen-induced arthritis (AIA), collagen antibody-induced arthritis (CAIA) and CIA [24][25][26][27]. The mechanisms underlying estrogenmediated inhibition of arthritis are still not fully elucidated; however, we recently reported that E2 regulates Th17 cell localization during development of CIA.…”

The interconnected role of chemokines and estrogen in bone metabolism

“…The CCR6-CCL20 pathway is expressed in Th17 cells, and this pathway facilitates the migration of Th17 cells to the site of inflammation (110). Estrogen augments the expression of CCR6 and CCL20 by Th17 cells in lymph nodes (LNs) through ERα, preventing the migration of Th17 cells to joints in established arthritis and resulting a higher level of Th17 cells in LNs and a lower level in joints (111). Estrogen affects the migration of Th17 cells via the CCR6 and CCL20 pathways while Th17 cells produce IL-17 to stimulate the expression of CXCL8, thus affecting the migration of neutrophils.…”

02.10 X-linked mirnas associated with gender differences in rheumatoid arthritis

“…First, hormones may play a role as hormonal changes during menopause or pregnancy impact RA severity. Estrogen treatment results in an increase in Th17 cells in lymph nodes during the early phase of development in experimental autoimmune arthritis [3]. Many studies focusing on the X chromosome-linked genes showed that differences in immune response and autoimmunity affecting Int.…”