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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2015

Open Access 01-12-2015 | Research article

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

Authors: Annica Andersson, Alexandra Stubelius, Merja Nurkkala Karlsson, Cecilia Engdahl, Malin Erlandsson, Louise Grahnemo, Marie K Lagerquist, Ulrika Islander

Published in: Arthritis Research & Therapy | Issue 1/2015

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Abstract

Introduction

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, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis.

Methods

Ovariectomized 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.

Results

E2-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.

Conclusions

This 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.
Appendix
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Literature
1.
Goemaere S, Ackerman C, Goethals K, De Keyser F, Van der Straeten C, Verbruggen G, et al. Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. J Rheumatol. 1990;17:1620–2.PubMed
2.
Khosla S, Melton 3rd LJ, Atkinson EJ, O’Fallon WM. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab. 2001;86:3555–61.CrossRefPubMed
3.
Ostensen M. Sex hormones and pregnancy in rheumatoid arthritis and systemic lupus erythematosus. Ann N Y Acad Sci. 1999;876:131–43. discussion 144.CrossRefPubMed
4.
Holmdahl R, Carlsten H, Jansson L, Larsson P. Oestrogen is a potent immunomodulator of murine experimental rheumatoid disease. Br J Rheumatol. 1989;28:54–8. discussion 69–71.CrossRefPubMed
5.
Engdahl C, Jochems C, Windahl SH, Börjesson AE, Ohlsson C, Carlsten H, et al. Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor α, and not estrogen receptor β or G protein-coupled receptor 30. Arthritis Rheum. 2010;62:524–33.PubMed
6.
D’Elia HF, Larsen A, Mattsson LA, Waltbrand E, Kvist G, Mellström D, et al. Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J Rheumatol. 2003;30:1456–63.PubMed
7.
Forsblad D’Elia H, Larsen A, Waltbrand E, Kvist G, Mellström D, Saxne T, et al. Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis. Ann Rheum Dis. 2003;62:617–23.CrossRefPubMed
8.
Yung RL. Mechanisms of lupus: the role of estrogens. Clin Exp Rheumatol. 1999;17:271–5.PubMed
9.
Rijhsinghani AG, Thompson K, Bhatia SK, Waldschmidt TJ. Estrogen blocks early T cell development in the thymus. Am J Reprod Immunol. 1996;36:269–77.CrossRefPubMed
10.
Erlandsson MC, Jonsson CA, Islander U, Ohlsson C, Carlsten H. Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice. Immunology. 2003;108:346–51.CrossRefPubMedCentralPubMed
11.
12.
Islander U, Erlandsson MC, Chavoshi T, Jochems C, Movérare S, Nilsson S, et al. Estren-mediated inhibition of T lymphopoiesis is estrogen receptor-independent whereas its suppression of T cell-mediated inflammation is estrogen receptor-dependent. Clin Exp Immunol. 2005;139:210–5.CrossRefPubMedCentralPubMed
13.
Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010;62:2876–85.CrossRefPubMed
14.
Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2:52ra72.CrossRefPubMed
15.
Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis. 2013;72:863–9.CrossRefPubMed
16.
Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood. 2010;115:335–43.CrossRefPubMed
17.
van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, et al. Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 2011;63:73–83.CrossRefPubMed
18.
Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103:1345–52.CrossRefPubMedCentralPubMed
19.
Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204:2803–12.CrossRefPubMedCentralPubMed
20.
Wang C, Dehghani B, Li Y, Kaler LJ, Vandenbark AA, Offner H. Oestrogen modulates experimental autoimmune encephalomyelitis and interleukin-17 production via programmed death 1. Immunology. 2009;126:329–35.CrossRefPubMedCentralPubMed
21.
Lélu K, Laffont S, Delpy L, Paulet PE, Périnat T, Tschanz SA, et al. Estrogen receptor α signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. J Immunol. 2011;187:2386–93.CrossRefPubMed
22.
Engdahl C, Börjesson AE, Forsman HF, Andersson A, Stubelius A, Krust A, et al. The role of total and cartilage-specific estrogen receptor α expression for the ameliorating effect of estrogen treatment on arthritis. Arthritis Res Ther. 2014;16:R150.CrossRefPubMedCentralPubMed
23.
Plum SM, Park EJ, Strawn SJ, Moore EG, Sidor CF, Fogler WE. Disease modifying and antiangiogenic activity of 2-methoxyestradiol in a murine model of rheumatoid arthritis. BMC Musculoskelet Disord. 2009;10:46.CrossRefPubMedCentralPubMed
24.
Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypes. Development. 2000;127:4277–91.PubMed
25.
Islander U, Jochems C, Stubelius A, Andersson A, Lagerquist MK, Ohlsson C, et al. Combined treatment with dexamethasone and raloxifene totally abrogates osteoporosis and joint destruction in experimental postmenopausal arthritis. Arthritis Res Ther. 2011;13:R96.CrossRefPubMedCentralPubMed
26.
Offner H, Adlard K, Zamora A, Vandenbark AA. Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis. J Clin Invest. 2000;105:1465–72.CrossRefPubMedCentralPubMed
27.
Van den Broeck W, Derore A, Simoens P. Anatomy and nomenclature of murine lymph nodes: descriptive study and nomenclatory standardization in BALB/cAnNCrl mice. J Immunol Methods. 2006;312:12–9.CrossRefPubMed
28.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25:402–8.CrossRefPubMed
29.
Webb A, Johnson A, Fortunato M, Platt A, Crabbe T, Christie MI, et al. Evidence for PI-3 K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists. J Leukoc Biol. 2008;84:1202–12.CrossRefPubMed
30.
Sato W, Aranami T, Yamamura T. Cutting edge: human Th17 cells are identified as bearing CCR2+CCR5− phenotype. J Immunol. 2007;178:7525–9.CrossRefPubMed
31.
Lim HW, Lee J, Hillsamer P, Kim CH. Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J Immunol. 2008;180:122–9.CrossRefPubMed
32.
33.
Cyster JG, Schwab SR. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol. 2012;30:69–94.CrossRefPubMed
34.
Bromley SK, Mempel TR, Luster AD. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol. 2008;9:970–80.CrossRefPubMed
35.
Mo R, Chen J, Grolleau-Julius A, Murphy HS, Richardson BC, Yung RL. Estrogen regulates CCR gene expression and function in T lymphocytes. J Immunol. 2005;174:6023–9.CrossRefPubMed
36.
Ho MF, Wang L, Weinshilboum R, Bongartz T. The rheumatoid arthritis risk locus CCR6 and its SNP-dependent response to estrogen: a possible genomic link between sex hormones and the IL-17 inflammatory pathway. Ann Rheum Dis. 2014;73:135. doi:10.1136/annrheumdis-2014-eular.5289.CrossRef
37.
Schutyser E, Struyf S, Van Damme J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 2003;14:409–26.CrossRefPubMed
38.
39.
Lengi AJ, Phillips RA, Karpuzoglu E, Ahmed SA. Estrogen selectively regulates chemokines in murine splenocytes. J Leukoc Biol. 2007;81:1065–74.CrossRefPubMed
40.
Wang F, Tan W, Guo D, He S. Reduction of CD4 positive T cells and improvement of pathological changes of collagen-induced arthritis by FTY720. Eur J Pharmacol. 2007;573:230–40.CrossRefPubMed
41.
Matsuyuki H, Maeda Y, Yano K, Sugahara K, Chiba K, Kohno T, et al. Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell Mol Immunol. 2006;3:429–37.PubMed
42.
Schulze T, Golfier S, Tabeling C, Räbel K, Gräler MH, Witzenrath M, et al. Sphingosine-1-phospate receptor 4 (S1P4) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model. FASEB J. 2011;25:4024–36.CrossRefPubMed
43.
Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One. 2012;7:e44552.CrossRefPubMedCentralPubMed
44.
Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012;13:991–9.CrossRefPubMedCentralPubMed
45.
Jochems C, Islander U, Erlandsson M, Verdrengh M, Ohlsson C, Carlsten H. Osteoporosis in experimental postmenopausal polyarthritis: the relative contributions of estrogen deficiency and inflammation. Arthritis Res Ther. 2005;7:R837–43.CrossRefPubMedCentralPubMed
46.
Niino M, Hirotani M, Fukazawa T, Kikuchi S, Sasaki H. Estrogens as potential therapeutic agents in multiple sclerosis. Cent Nerv Syst Agents Med Chem. 2009;9:87–94.CrossRefPubMed
47.
DeSelm CJ, Takahata Y, Warren J, Chappel JC, Khan T, Li X, et al. IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. J Cell Biochem. 2012;113:2895–902.CrossRefPubMedCentralPubMed
Metadata
Title
Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis
Authors
Annica Andersson
Alexandra Stubelius
Merja Nurkkala Karlsson
Cecilia Engdahl
Malin Erlandsson
Louise Grahnemo
Marie K Lagerquist
Ulrika Islander
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2015
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-015-0548-y

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