Abstract
Immunoproteasome activation in immune cells is involved in the modulation of immune responses. Increasing evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases, but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjögren’s syndrome (SS). Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS (ESS) in mice. In this study, we detected high levels of low-molecular-weight protein 7 (LMP7), a key subunit of the immunoproteasome, in Th17 cells from ESS mice. Moreover, treatment with bortezomib (BTZ), a proteasome inhibitor, markedly suppressed Th17 differentiation in both murine and human naive T cells in culture. Furthermore, ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS mice. Notably, BTZ-treated ESS mice showed markedly decreased Th17 cells, germinal center B cells and plasma cells in the peripheral lymphoid organs. In addition, adoptively transferred wild type naive CD4+ T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS induction. However, BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient mice. Taken together, our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response, which may contribute to the development of a novel therapeutic strategy for the treatment of SS.
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References
Fox RI . Sjögren’s syndrome. Lancet 2005; 366: 321–331.
Adamson TC, Fox R, Frisman D, Howell F . Immunohistologic analysis of lymphoid infiltrates in primary Sjogren’s syndrome using monoclonal antibodies. J Immunol 1983; 130: 203–208.
Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM . Characteristics of the minor salivary gland infiltrates in Sjogren’s syndrome. J Autoimmun 2010; 34: 400–407.
Fox RI, Carstens SA, Fong S, Robinson CA, Howell F, Vaughan JH . Use of monoclonal antibodies to analyze peripheral blood and salivary gland lymphocyte subsets in Sjögren’s syndrome. Arthritis Rheum 1982; 25: 419–426.
Talal N, Sylvester RA, Daniels TE, Greenspan JS, Williams RC Jr . T and B lymphocytes in peripheral blood and tissue lesions in Sjögren’s syndrome. J Clin Invest 1974; 53: 180.
Youinou P, Pers J-O . Disturbance of cytokine networks in Sjögren’s syndrome. Arthritis Res Ther 2011; 13: 227.
Youinou P, Devauchelle-Pensec V, Pers JO . Significance of B cells and B cell clonality in Sjögren’s syndrome. Arthritis Rheum 2010; 62: 2605–2610.
Dong C . Targeting Th17 cells in immune diseases. Cell Res 2014; 24: 901–903.
Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 2011; 472: 486–490.
Wang D, Huang S, Yuan X, Liang J, Xu R, Yao G et al. The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus. Cell Mol Immunol 2015 e-pub ahead of print 5 October 2015 doi:10.1038/cmi.2015.89.
Rui K, Zhang Z, Tian J, Lin X, Wang X, Ma J et al. Olfactory ecto-mesenchymal stem cells possess immunoregulatory function and suppress autoimmune arthritis. Cell Mol Immunol 2016; 13: 401–408.
Lin X, Rui K, Deng J, Tian J, Wang X, Wang S et al. Th17 cells play a critical role in the development of experimental Sjogren’s syndrome. Ann Rheum Dis 2015; 74: 1302–1310.
Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M et al. Efficacy and safety of belimumab in primary Sjögren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis 2013; 74: 526–531.
Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N et al. Effectiveness of rituximab treatment in primary Sjogren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010; 62: 960–968.
Steinfeld SD, Tant L, Burmester GR, Teoh NK, Wegener WA, Goldenberg DM et al. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren’s syndrome: an open-label phase I/II study. Arthritis Res Ther 2006; 8: 1.
Verbrugge SE, Scheper RJ, Lems WF, de Gruijl TD, Jansen G . Proteasome inhibitors as experimental therapeutics of autoimmune diseases. Arthritis Res Ther 2015; 17: 1186.
Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH . Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107: 4907–4916.
Muchamuel T, Basler M, Aujay MA, Suzuki E, Kalim KW, Lauer C et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 2009; 15: 781–787.
Lee S-W, Kim J-H, Park Y-B, Lee S-K . Bortezomib attenuates murine collagen-induced arthritis. Ann Rheum Dis 2009; 68: 1761–1767.
Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 2008; 14: 748–755.
Ichikawa HT, Conley T, Muchamuel T, Jiang J, Lee S, Owen T et al. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum 2012; 64: 493–503.
Alexander T, Sarfert R, Klotsche J, Kühl AA, Rubbert-Roth A, Lorenz H-M et al. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 2015; 74: 1474–1478.
Basler M, Mundt S, Muchamuel T, Moll C, Jiang J, Groettrup M et al. Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis. EMBO Mol Med 2014; 6: 226–238.
Martinez-Gamboa L, Lesemann K, Kuckelkorn U, Scheffler S, Ghannam K, Hahne M et al. Gene expression of catalytic proteasome subunits and resistance toward proteasome inhibition of B lymphocytes from patients with primary Sjögren syndrome. J Rheumatol 2013; 40: 663–673.
Egerer T, Martinez-Gamboa L, Dankof A, Stuhlmüller B, Dörner T, Krenn V et al. Tissue-specific up-regulation of the proteasome subunit β5i (LMP7) in Sjögren’s syndrome. Arthritis Rheum 2006; 54: 1501–1508.
Lin X, Rui K, Deng J, Tian J, Wang X, Wang S et al. Th17 cells play a critical role in the development of experimental Sjogren’s syndrome. Ann Rheum Dis 2014; 74: 1302–1310.
Scardina GA, Spanò G, Carini F, Spicola M, Valenza V, Messina P et al. Diagnostic evaluation of serial sections of labial salivary gland biopsies in Sjögren s syndrome. Med Oral Patol Oral Cir Bucal 2007; 12: 565–568.
Yang M, Sun L, Wang S, Ko KH, Xu H, Zheng BJ et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J Immunol 2010; 184: 3321–3325.
Yang M, Deng J, Liu Y, Ko KH, Wang X, Jiao Z et al. IL-10-producing regulatory B10 cells ameliorate collagen-induced arthritis via suppressing Th17 cell generation. Am J Pathol 2012; 180: 2375–2385.
Costa S, Schutz S, Cornec D, Uguen A, Quintin-Roue I, Lesourd A et al. B-cell and T-cell quantification in minor salivary glands in primary Sjogren’s syndrome: development and validation of a pixel-based digital procedure. Arthritis Res Ther 2016; 18: 21.
Noack M, Miossec P . Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014; 13: 668–677.
Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012; 120: 947–959.
Groettrup M, Kirk CJ, Basler M . Proteasomes in immune cells: more than peptide producers? Nat Rev Immunol 2010; 10: 73–78.
Kalim KW, Basler M, Kirk CJ, Groettrup M . Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiation. J Immunol 2012; 189: 4182–4193.
Schmidt N, Gonzalez E, Visekruna A, Kühl AA, Loddenkemper C, Mollenkopf H et al. Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis. Gut 2010; 59: 896–906.
Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM . Systemic and local interleukin-17 and linked cytokines associated with Sjögren’s syndrome immunopathogenesis. Am J Pathol 2009; 175: 1167–1177.
Alunno A, Carubbi F, Bistoni O, Caterbi S, Bartoloni E, Bigerna B et al. CD4(−)CD8(−) T-cells in primary Sjogren’s syndrome: association with the extent of glandular involvement. J Autoimmun 2014; 51: 38–43.
De Paiva C, Chotikavanich S, Pangelinan S, Pitcher J, Fang B, Zheng X et al. IL-17 disrupts corneal barrier following desiccating stress. Mucosal Immunol 2009; 2: 243–253.
Nguyen C, Yin H, Lee BH, Carcamo W, Chiorini J, Peck A . Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther 2010; 12: R220.
Turpie B, Yoshimura T, Gulati A, Rios JD, Dartt DA, Masli S . Sjögren’s syndrome-like ocular surface disease in thrombospondin-1 deficient'mice. Am J Pathol 2009; 175: 1136–1147.
Naito Y, Matsumoto I, Wakamatsu E, Goto D, Sugiyama T, Matsumura R et al. Muscarinic acetylcholine receptor autoantibodies in patients with Sjögren’s syndrome. Ann Rheum Dis 2005; 64: 510–511.
Scagliusi P, D’Amore M, D’Amore S, Scagliusi A . Sjogren’s syndrome: apoptosis by anti-SSA and anti-SSB antibodies. Reumatismo 2006; 58: 165–166.
Sumida T, Tsuboi H, Iizuka M, Asashima H, Matsumoto I . Anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren’s syndrome. Mod Rheumatol 2013; 23: 841–845.
Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 2016; 76: 9–16.
Hickman-Brecks CL, Racz JL, Meyer DM, LaBranche TP, Allen PM . Th17 cells can provide B cell help in autoantibody induced arthritis. J Autoimmun 2011; 36: 65–75.
Lai Kwan Lam Q, King Hung Ko O, Zheng BJ, Lu L . Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis. Proc Natl Acad Sci USA 2008; 105: 14993–14998.
Wang X, Ma K, Chen M, Ko KH, Zheng BJ, Lu L . IL-17A promotes pulmonary B-1a cell differentiation via induction of Blimp-1 expression during influenza virus infection. PLoS Pathog 2016; 12: e1005367.
Basler M, Dajee M, Moll C, Groettrup M, Kirk CJ . Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J Immunol 2010; 185: 634–641.
Jakez-Ocampo J, Atisha-Fregoso Y, Llorente L . Refractory primary sjögren syndrome successfully treated with bortezomib. J Clin Rheumatol 2015; 21: 31–32.
Chen D, Frezza M, Schmitt S, Kanwar J, Dou Q . Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 2011; 11: 239.
Schrader J, Henneberg F, Mata RA, Tittmann K, Schneider TR, Stark H et al. The inhibition mechanism of human 20S proteasomes enables next-generation inhibitor design. Science 2016; 353: 594–598.
Acknowledgements
We thank the technical support and service of the Medical Faculty Core Facility and Laboratory Animal Unit in The University of Hong Kong. This study was supported by grants from the National Natural Science Foundation of China (81373195, 91442116, 81601424 and 31300739), the National Basic Research Program (No. 2014CB541904), the Natural Science Foundation of Jiangsu (Grant No. BK20150533), the General Research Fund, Hong Kong Research Grants Council (No. 17114515; 17149716); and the Hong Kong Croucher Foundation (260960116).
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Xiao, F., Lin, X., Tian, J. et al. Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome. Cell Mol Immunol 14, 924–934 (2017). https://doi.org/10.1038/cmi.2017.8
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DOI: https://doi.org/10.1038/cmi.2017.8
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