The correlation between the Th17/Treg cell balance and bone health

Lei Zhu1, Hua Fang1, Wenge Ding1, Kai Ding1, Yige Zhang1, Chenyang Xu1
1The Third Affiliated Hospital of Soochow University, The First People’s Hospital of Changzhou, Jiangsu, 213003, China

Tóm tắt

Abstract

With the ageing of the world population, osteoporosis has become a problem affecting quality of life. According to the traditional view, the causes of osteoporosis mainly include endocrine disorders, metabolic disorders and mechanical factors. However, in recent years, the immune system and immune factors have been shown to play important roles in the occurrence and development of osteoporosis. Among these components, regulatory T (Treg) cells and T helper 17 (Th17) cells are crucial for maintaining bone homeostasis, especially osteoclast differentiation. Treg cells and Th17 cells originate from the same precursor cells, and their differentiation requires involvement of the TGF-β regulated signalling pathway. Treg cells and Th17 cells have opposite functions. Treg cells inhibit the differentiation of osteoclasts in vivo and in vitro, while Th17 cells promote the differentiation of osteoclasts. Therefore, understanding the balance between Treg cells and Th17 cells is anticipated to provide a new idea for the development of novel treatments for osteoporosis.

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Tài liệu tham khảo

Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019;393(10169):364–76.

Dar H, Azam Z, Anupam R, Mondal R, Srivastava R. Osteoimmunology: the Nexus between bone and immune system. Front Biosci. 2018;23:464–92.

Srivastava RK, Dar HY, Mishra PK. Immunoporosis: immunology of osteoporosis-role of T cells. Front Immunol. 2018;9:657.

Arron JR, Choi Y. Bone versus immune system. Nature. 2000;408(6812):535–6.

Dar HY, Azam Z, Anupam R, Mondal RK, Srivastava RK. Osteoimmunology: The Nexus between bone and immune system. Front Biosci. 2018;23:464–92.

Bozec A, Zaiss MM. T regulatory cells in bone Remodelling. Curr Osteoporos Rep. 2017;15(3):121–5.

Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7(4):292–304.

Takayanagi H. The unexpected link between osteoclasts and the immune system. Oxygen Transpor Tissue XXXIII. 2010;658:61–8.

Takayanagi H, Sato K, Takaoka A, Taniguchi T. Interplay between interferon and other cytokine systems in bone metabolism. Immunol Rev. 2005;208(1):181–93.

Ross FP, Teitelbaum SL. alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev. 2006;208(1):88–105.

Vries T, Bakkali I, Kamradt T, Schett G, Jansen I, d'amelio P. What Are the Peripheral Blood Determinants for Increased Osteoclast Formation in the Various Inflammatory Diseases Associated With Bone Loss? Front Immunol. 2019:10.

Sakaguchi S. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol (Baltimore, Md : 1950). 1995;3(155):1154–64.

Shao TY, Hsu LH, Chien CH, Chiang BL. Novel Foxp3(−) IL-10(−) regulatory T-cells induced by B-cells alleviate intestinal inflammation in vivo. Sci Rep. 2016;6:32415.

Yu M, D'Amelio P, Tyagi AM, Vaccaro C, Li JY, Hsu E, et al. Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice. EMBO Rep. 2018;19(1):156–71.

Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, et al. Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev. 2017;97(4):1295–349.

Zaiss MM, Axmann R, Zwerina J, Polzer K, Guckel E, Skapenko A, et al. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum. 2007;56(12):4104–12.

Yuan FL, Li X, Lu WG, Xu RS, Zhao YQ, Li CW, et al. Regulatory T cells as a potent target for controlling bone loss. Biochem Biophys Res Commun. 2010;402(2):173–6.

Fischer L, Herkner C, Kitte R, Dohnke S, Riewaldt J, Kretschmer K, et al. Foxp3+ Regulatory T Cells in Bone and Hematopoietic Homeostasis. Front Endocrinol. 2019;10(578).

Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-β: the role of T regulatory cells. Immunology. 2006;117(4):433–42.

Oh S, Rankin AL, Caton AJ. CD4+CD25+ regulatory T cells in autoimmune arthritis. Immunol Rev. 2010;233(1):97–111.

Kelchtermans H, Geboes L, Mitera T, Huskens D, Leclercq G, Matthys P. Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis. Ann Rheumatic Dis. 68(5):744–50.

Tanaka Y. Clinical immunity in bone and joints. J Bone Miner Metab. 2019;37(1):2–8.

Runyan CE, Liu Z, Schnaper HW. Phosphatidylinositol-3-kinase and Rab5 inversely regulate the Smad anchor for receptor activation (SARA) protein independently of TGF-[beta]1. J Biol Chem. 2012.

Zhao L, Jiang S, Hantash B. Transforming growth factor β1 induces Osteogenic differentiation of murine bone marrow stromal cells. Tissue Eng A. 2009;16:725–33.

Tyagi AM, Yu M, Darby TM, Vaccaro C, Li JY, Owens JA, et al. The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression. Immunity. 2018;49(6):1116–31 e7.

Shashkova EV, Trivedi J, Cline-Smith AB, Ferris C, Buchwald ZS, Gibbs J, et al. Osteoclast-primed Foxp3<sup>+</sup> CD8 T cells induce T-bet, Eomesodermin, and IFN-γ to regulate bone Resorption. J Immunol. 2016;197(3):726–35.

Niederkorn JY. Emerging concepts in CD8+ T regulatory cells. Curr Opin Immunol. 2008;20(3):327–31.

You L, Chen L, Pan L, Peng Y, Chen J. SOST gene inhibits Osteogenesis from adipose-derived Mesenchymal stem cells by inducing Th17 cell differentiation. Cell Physiol Biochem. 2018;48(3):1030–40.

Li Q, Wang B, Mu K, Zhang JA. The pathogenesis of thyroid autoimmune diseases: new T lymphocytes - cytokines circuits beyond the Th1-Th2 paradigm. J Cell Physiol. 2019;234(3):2204–16.

Ono T, Takayanagi H. Osteoimmunology in bone fracture healing. Curr Osteoporos Rep. 2017;15(4):367–75.

Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2014;74(1):5–17.

Xiong J, Piemontese M, Thostenson JD, Weinstein RS, Manolagas SC, O'Brien CA. Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency. Bone. 2014;66:146–54.

Bandyopadhyay S, Lion J-M, Mentaverri R, Ricupero DA, Kamel S, Romero JR, et al. Attenuation of osteoclastogenesis and osteoclast function by apigenin. Biochem Pharmacol. 2006;72(2):184–97.

Oukka M. Interplay between pathogenic Th17 and regulatory T cells. Ann Rheum Dis. 2007;66(Suppl 3):iii87–90.

Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.

Kyburz D, Corr M. Th17 cells generated in the absence of TGF-β induce experimental allergic encephalitis upon adoptive transfer. Exp Rev Clin Immunol. 2011;7(3):283–5.

Sun L, Fu J, Zhou Y. Metabolism controls the balance of Th17/T-regulatory cells. Front Immunol. 2017;8:1632.

Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, et al. CD39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol. 2009;183(11):7602–10.

Ueno A, Ghosh A, Hung D, Li J, Jijon H. Th17 plasticity and its changes associated with inflammatory bowel disease. World J Gastroenterol. 2015;21(43):12283–95.

Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, et al. Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs. Immunity. 2008;29(1):44–56.

Deknuydt F, Bioley G, Valmori D, Ayyoub M. IL-1beta and IL-2 convert human Treg into T(H)17 cells. Clin Immunol. 2009;131(2):298–307.

Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM, et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol. 2018;15(5):458–69.

Gruber R. Osteoimmunology: inflammatory osteolysis and regeneration of the alveolar bone. J Clin Periodontol. 2019;46(Suppl 21):52–69.

Jiao WE, Wei JF, Kong YG, Xu Y, Tao ZZ, Chen SM. Notch signaling promotes development of allergic rhinitis by suppressing Foxp3 expression and Treg cell differentiation. Int Arch Allergy Immunol. 2019;178(1):33–44.

Li C, Sheng A, Jia X, Zeng Z, Zhang X, Zhao W, et al. Th17/Treg dysregulation in allergic asthmatic children is associated with elevated notch expression. J Asthma. 2018;55(1):1–7.

Yin X, Wei H, Wu S, Wang Z, Liu B, Guo L, et al. DAPT reverses the Th17/Treg imbalance in experimental autoimmune uveitis in vitro via inhibiting notch signaling pathway. Int Immunopharmacol. 2019;79:106107.

Qin L, Zhou YC, Wu HJ, Zhuo Y, Wang YP, Si CY, et al. Notch signaling modulates the balance of regulatory T cells and T helper 17 cells in patients with chronic hepatitis C. DNA Cell Biol. 2017;36(4):311–20.

Mijailovic I, Nikolic N, Djinic A, Carkic J, Milinkovic I, Peric M, et al. The down-regulation of notch 1 signaling contributes to the severity of bone loss in aggressive periodontitis. J Periodontol. 2020;91(4):554–61.

Li MO, Rudensky AY. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat Rev Immunol. 2016;16(4):220–33.

Brisslert M, Bian L, Svensson MN, Santos RF, Jonsson IM, Barsukov I, et al. S100A4 regulates the Src-tyrosine kinase dependent differentiation of Th17 cells in rheumatoid arthritis. Biochim Biophys Acta. 2014;1842(11):2049–59.

Picard C, Dogniaux S, Chemin K, Maciorowski Z, Lim A, Mazerolles F, et al. Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity. Eur J Immunol. 2009;39(7):1966–76.

Cibrian D, Castillo-Gonzalez R, Fernandez-Gallego N, de la Fuente H, Jorge I, Saiz ML, et al. Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation. J Allergy Clin Immunol. 2020;145(1):199–214 e11.

Hwang S, Song K-D, Lesourne R, Lee J, Pinkhasov J, Li L, et al. Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease. J Exp Med. 2012;209(10):1781–95.

Kemp KL, Levin SD, Stein PL. Lck regulates IL-10 expression in memory-like Th1 cells. Eur J Immunol. 2010;40(11):3210–9.

Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol. 2011;12(4):304–11.

Sidwell T, Liao Y, Garnham AL, Vasanthakumar A, Gloury R, Blume J, et al. Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis. Nat Commun. 2020;11(1):252.

Gibson SA, Yang W, Yan Z, Qin H, Benveniste EN. CK2 controls Th17 and regulatory T cell differentiation through inhibition of FoxO1. J Immunol. 2018;201(2):383–92.

Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, et al. B7/CD28 Costimulation is essential for the homeostasis of the CD4+CD25+ Immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12(4):431–40.

Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA. CD28 Costimulation: From Mechanism to Therapy. Immunity. 44(5):973–88.

Tai X, Cowan M, Feigenbaum L, Singer A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol. 2005;6(2):152–62.

Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA. An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest. 2013;123(2):580–93.

Bouguermouh S, Fortin G, Baba N, Rubio M, Sarfati M. CD28 co-stimulation down regulates Th17 development. PLoS One. 2009;4(3):e5087.

Liao W, Lin J-X, Wang L, Li P, Leonard WJ. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol. 2011;12(6):551–9.

MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013;31:259–83.

Hongbo C. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 2012;5(12):325–38.

Cluxton D, Petrasca A, Moran B, Fletcher JM. Differential regulation of human Treg and Th17 cells by fatty acid synthesis and glycolysis. Front Immunol. 2019;10:115.

Polzonetti V, Pucciarelli S, Vincenzetti S, Polidori P. Dietary Intake of Vitamin D from Dairy Products Reduces the Risk of Osteoporosis. Nutrients. 2020;12(6):1743.

Dar HY, Singh A, Shukla P, Anupam R, Mondal RK, Mishra PK, et al. High dietary salt intake correlates with modulated Th17-Treg cell balance resulting in enhanced bone loss and impaired bone-microarchitecture in male mice. Sci Rep. 2018;8(1):2503.

Yang YH, Istomine R, Alvarez F, Al-Aubodah TA, Shi XQ, Takano T, et al. Salt sensing by serum/glucocorticoid-regulated kinase 1 promotes Th17-like inflammatory adaptation of Foxp3(+) regulatory T cells. Cell Rep. 2020;30(5):1515–29 e4.

Wu L, Luthringer BJC, Feyerabend F, Zhang Z, Machens HG, Maeda M, et al. Increased levels of sodium chloride directly increase osteoclastic differentiation and resorption in mice and men. Osteoporos Int. 2017;28(11):3215–28.

Schröder A, Neubert P, Titze J, Bozec A, Neuhofer W, Proff P, et al. Osteoprotective action of low-salt diet requires myeloid cell–derived NFAT5. JCI Insight. 2019;4(23).

Antonios TF, Macgregor GA. Salt--more adverse effects. Am J Hypertens. 1997;10(5):250–1.

Pao-Hwa L, Fiona G, Appel LJ, Mikel A, Arline B, Patrick G, et al. The DASH diet and sodium reduction improve markers of bone turnover and calcium metabolism in adults. J Nutr. 2003;133(10):3130–6.

Hu ED, Chen DZ, Wu JL, Lu FB, Chen L, Zheng MH, et al. High fiber dietary and sodium butyrate attenuate experimental autoimmune hepatitis through regulation of immune regulatory cells and intestinal barrier. Cell Immunol. 2018;328:24–32.

Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446–50.

Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40(1):128–39.

Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341(6145):569–73.

Haase S, Haghikia A, Wilck N, Muller DN, Linker RA. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology. 2018;154(2):230–8.

Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317(5835):256–60.

Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204(8):1775–85.

Schilderink R, Verseijden C, Seppen J, Muncan V, van den Brink GR, Lambers TT, et al. The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC. Am J Physiol Gastrointest Liver Physiol. 2016;310(11):G1138–46.

Tanoue T, Atarashi K, Honda K. Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol. 2016;16(5):295–309.

Caspar O. MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt? T cells. Science (New York, NY). 2015;6251(349):989–93.

Peter J, Sabu V, Aswathy IS, Krishnan S, Lal Preethi SS, Simon M, et al. Dietary amaranths modulate the immune response via balancing Th1/Th2 and Th17/Treg response in collagen-induced arthritis. Mol Cell Biochem. 2020.

Ibáñez L, Rouleau M, Wakkach A, Blin-Wakkach C. Gut microbiome and bone. Joint Bone Spine. 2019;86(1):43–7.

Estrada JA, Contreras I. Nutritional Modulation of Immune and Central Nervous System Homeostasis: The Role of Diet in Development of Neuroinflammation and Neurological Disease. Nutrients. 2019;11(5):1076.

Donkor ON, Ravikumar M, Proudfoot O, Day SL, Apostolopoulos V, Paukovics G, et al. Cytokine profile and induction of T helper type 17 and regulatory T cells by human peripheral mononuclear cells after microbial exposure. Clin Exp Immunol. 2012;167(2):282–95.

Yu R, Zuo F, Ma H, Chen S. Exopolysaccharide-Producing Bifidobacterium adolescentis Strains with Similar Adhesion Property Induce Differential Regulation of Inflammatory Immune Response in Treg/Th17 Axis of DSS-Colitis Mice. Nutrients. 2019;11(4):782.

Onuora S. Autoimmunity: human gut bacteria induce TH17 cells. Nat Rev Rheumatol. 2016;13(1):2.

Cheng J, Guan, Chen Q, Shujiao M. The Th17/Treg Cell Balance: A Gut Microbiota-Modulated Story. Microorganisms. 2019;7:583.

Dar HY, Pal S, Shukla P, Mishra PK, Tomar GB, Chattopadhyay N, et al. Bacillus clausii inhibits bone loss by skewing Treg-Th17 cell equilibrium in postmenopausal osteoporotic mice model. Nutrition. 2018;54:118–28.

Jang YJ, Kim WK, Han DH, Lee K, Ko G. Lactobacillus fermentum species ameliorate dextran sulfate sodium-induced colitis by regulating the immune response and altering gut microbiota. Gut Microbes. 2019;10(6):696–711.

Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, et al. Control of T (reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453(7191):65–71.

Xiong L, Dean J, Fu Z, Oliff K, Bostick J, Ye J, et al. Ahr-Foxp3-RORγt axis controls gut homing of CD4 + T cells by regulating GPR15. Sci Immunol. 2020;5:eaaz7277.

Carriche GM, Almeida L, Stuve P, Velasquez L, Dhillon-LaBrooy A, Roy U, et al. Regulating T-cell differentiation through the polyamine spermidine. J Allergy Clin Immunol. 2020.

Kochetkova I, Thornburg T, Callis G, Holderness K, Maddaloni M, Pascual DW. Oral Escherichia coli colonization factor antigen I fimbriae ameliorate arthritis via IL-35, not IL-27. J Immunol. 2014;192(2):804–16.

Ding K, Hua F, Ding W. Gut microbiome and osteoporosis. Aging Dis. 2020;11(2):438–47.