Advertisement

Molecular Neurobiology

, Volume 54, Issue 7, pp 4908–4920 | Cite as

Adiponectin Suppresses T Helper 17 Cell Differentiation and Limits Autoimmune CNS Inflammation via the SIRT1/PPARγ/RORγt Pathway

  • Kai Zhang
  • Yawei Guo
  • Zhenzhen Ge
  • Zhihui Zhang
  • Yurong Da
  • Wen Li
  • Zimu Zhang
  • Zhenyi Xue
  • Yan Li
  • Yinghui Ren
  • Long Jia
  • Koon-Ho Chan
  • Fengrui Yang
  • Jun Yan
  • Zhi Yao
  • Aimin Xu
  • Rongxin ZhangEmail author
Article

Abstract

T helper 17 (Th17) cells are vital components of the adaptive immune system involved in the pathogenesis of most autoimmune and inflammatory syndromes, and adiponectin(ADN) is correlated with inflammatory diseases such as multiple sclerosis (MS) and type II diabetes. However, the regulatory effects of adiponectin on pathogenic Th17 cell and Th17-mediated autoimmune central nervous system (CNS) inflammation are not fully understood. In this study, we demonstrated that ADN could inhibit Th1 and Th17 but not Th2 cells differentiation in vitro. In the in vivo study, we demonstrated that ADN deficiency promoted CNS inflammation and demyelination and exacerbated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Furthermore, ADN deficiency increased the Th1 and Th17 cell cytokines of both the peripheral immune system and CNS in mice suffering from EAE. It is worth mentioning that ADN deficiency predominantly promoted the antigen-specific Th17 cells response in autoimmune encephalomyelitis. In addition, in vitro and in vivo, ADN upregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ (PPARγ) and inhibited retinoid-related orphan receptor-γt (RORγt); the key transcription factor during Th17 cell differentiation. These results systematically uncovered the role and mechanism of adiponectin on pathogenic Th17 cells and suggested that adiponectin could inhibit Th17 cell-mediated autoimmune CNS inflammation.

Keywords

Adiponectin Th17 cell Experimental autoimmune encephalomyelitis SIRT1 PPARγ RORγt 

Abbreviations

ADN

Adiponectin

Th

T helper

CNS

Central nervous system

IL

Interleukin

TNF-α

Tumor necrosis factor-α

IFN-γ

Interferon-γ

MS

Multiple sclerosis

EAE

Experimental autoimmune encephalomyelitis

MOG

Myelin oligodendrocyte glycoprotein

H&E

Hematoxylin-eosin

ELISA

Enzyme-linked immunosorbent assay

STAT

Signal transducer and activator of transcription

T-bet

T box transcription factor

AMPK

Adenosine monophosphate-activated protein kinase

SIRT1

Sirtuin 1

PPARγ

Peroxisome proliferator-activated receptor γ

RORγt

Retinoid-related orphan receptor-γt

Notes

Acknowledgments

This work was supported by the Ministry of Science and Technology of China through Grant No. 2012CB932503; the National Natural Science Foundation of China through Grants No. 91029705, 81172864, 81272317, 81302568, 81301026, and 31402097.

Compliance with Ethical Standards

The care and treatment for mice were approved by Animal Ethics Committee of Tianjin Medical University and were in accordance with guidelines for animal care.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117:515–526CrossRefPubMedGoogle Scholar
  2. 2.
    Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jutel M, Akdis CA (2011) T-cell subset regulation in atopy. Curr Allergy Asthma Rep 11:139–145CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Coffman RL, Carty J (1986) A T cell activity that enhances polyclonal IgE production and its inhibition by interferon-gamma. J Immunol 136:949–954PubMedGoogle Scholar
  5. 5.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, et al. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133CrossRefPubMedGoogle Scholar
  7. 7.
    Yang J, Sundrud MS, Skepner J, Yamagata T (2014) Targeting Th17 cells in autoimmune diseases. Trends Pharmacol Sci 35:493–500CrossRefPubMedGoogle Scholar
  8. 8.
    McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919CrossRefPubMedGoogle Scholar
  9. 9.
    Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F (2005) IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol 174:3695–3702CrossRefPubMedGoogle Scholar
  10. 10.
    Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517CrossRefPubMedGoogle Scholar
  11. 11.
    Segal BM (2010) Th17 cells in autoimmune demyelinating disease. Semin Immunopathol 32:71–77CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Algood HM, Allen SS, Washington MK, Peek RM Jr, Miller GG, Cover TL (2009) Regulation of gastric B cell recruitment is dependent on IL-17 receptor a signaling in a model of chronic bacterial infection. J Immunol 183:5837–5846CrossRefPubMedGoogle Scholar
  13. 13.
    Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, et al. (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508CrossRefPubMedGoogle Scholar
  14. 14.
    Schraml BU, Hildner K, Ise W, Lee WL, Smith WA, Solomon B, Sahota G, Sim J, et al. (2009) The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460:405–409PubMedPubMedCentralGoogle Scholar
  15. 15.
    Hu Y, Ota N, Peng I, Refino CJ, Danilenko DM, Caplazi P, Ouyang W (2010) IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol 184:4307–4316CrossRefPubMedGoogle Scholar
  16. 16.
    Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783CrossRefPubMedGoogle Scholar
  17. 17.
    Wolf AM, Wolf D, Avila MA, Moschen AR, Berasain C, Enrich B, Rumpold H, Tilg H (2006) Upregulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J Hepatol 44:537–543CrossRefPubMedGoogle Scholar
  18. 18.
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, et al. (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83CrossRefPubMedGoogle Scholar
  19. 19.
    Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, et al. (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866CrossRefPubMedGoogle Scholar
  20. 20.
    Hatano Y, Matsumoto M, Ishikawa S, Kajii E (2009) Plasma adiponectin level and myocardial infarction: the JMS cohort study. J Epidemiol 19:49–55CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Nishihara T, Matsuda M, Araki H, Oshima K, Kihara S, Funahashi T, Shimomura I (2006) Effect of adiponectin on murine colitis induced by dextran sulfate sodium. Gastroenterology 131:853–861CrossRefPubMedGoogle Scholar
  22. 22.
    Parker J, Menn-Josephy H, Laskow B, Takemura Y, Aprahamian T (2011) Modulation of lupus phenotype by adiponectin deficiency in autoimmune mouse models. J Clin Immunol 31:167–173CrossRefPubMedGoogle Scholar
  23. 23.
    Musabak U, Demirkaya S, Genc G, Ilikci RS, Odabasi Z (2011) Serum adiponectin, TNF-alpha, IL-12p70, and IL-13 levels in multiple sclerosis and the effects of different therapy regimens. Neuroimmunomodulation 18:57–66CrossRefPubMedGoogle Scholar
  24. 24.
    Kaur S, Zilmer K, Leping V, Zilmer M (2011) The levels of adiponectin and leptin and their relation to other markers of cardiovascular risk in patients with psoriasis. J Eur Acad Dermatol Venereol 25:1328–1333CrossRefPubMedGoogle Scholar
  25. 25.
    Matarese G, Carrieri PB, La Cava A, Perna F, Sanna V, De Rosa V, Aufiero D, Fontana S, et al. (2005) Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci U S A 102:5150–5155CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Matarese G, Di Giacomo A, Sanna V, Lord GM, Howard JK, Di Tuoro A, Bloom SR, Lechler RI, et al. (2001) Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 166:5909–5916CrossRefPubMedGoogle Scholar
  27. 27.
    Piccio L, Cantoni C, Henderson JG, Hawiger D, Ramsbottom M, Mikesell R, Ryu J, Hsieh CS, et al. (2013) Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis. Eur J Immunol 43:2089–2100CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jung MY, Kim HS, Hong HJ, Youn BS, Kim TS (2012) Adiponectin induces dendritic cell activation via PLCgamma/JNK/NF-kappaB pathways, leading to Th1 and Th17 polarization. J Immunol 188:2592–2601CrossRefPubMedGoogle Scholar
  29. 29.
    Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, et al. (2013) A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503:493–499CrossRefPubMedGoogle Scholar
  30. 30.
    Huang B, Cheng X, Wang D, Peng M, Xue Z, Da Y, Zhang N, Yao Z, et al. (2014) Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1alpha signaling. Oncotarget 5:4732–4745CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Vachharajani VT, Liu T, Wang X, Hoth JJ, Yoza BK, McCall CE (2016) Sirtuins link inflammation and metabolism. J Immunol Res 8167273:20Google Scholar
  32. 32.
    Park SY, Lee SW, Kim HY, Lee SY, Lee WS, Hong KW, Kim CD (2016) SIRT1 inhibits differentiation of monocytes to macrophages: amelioration of synovial inflammation in rheumatoid arthritis. J Mol Med 9:9Google Scholar
  33. 33.
    Choi YH, Bae JK, Chae HS, Kim YM, Sreymom Y, Han L, Jang HY, Chin YW (2015) Alpha-Mangostin regulates hepatic steatosis and obesity through SirT1-AMPK and PPARgamma pathways in high-fat diet-induced obese mice. J Agric Food Chem 63:8399–8406CrossRefPubMedGoogle Scholar
  34. 34.
    Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I (2003) Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52:1655–1663CrossRefPubMedGoogle Scholar
  35. 35.
    Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, et al. (2001) PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094–2099CrossRefPubMedGoogle Scholar
  36. 36.
    Yu JG, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, Sinha M, Olefsky JM (2002) The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51:2968–2974CrossRefPubMedGoogle Scholar
  37. 37.
    Bodles AM, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ (2006) Pioglitazone increases secretion of high-molecular-weight adiponectin from adipocytes. Am J Physiol Endocrinol Metab 291:27CrossRefGoogle Scholar
  38. 38.
    Klotz L, Burgdorf S, Dani I, Saijo K, Flossdorf J, Hucke S, Alferink J, Nowak N, et al. (2009) The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med 206:2079–2089CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wong WT, Tian XY, Xu A, Yu J, Lau CW, Hoo RL, Wang Y, Lee VW, et al. (2011) Adiponectin is required for PPARgamma-mediated improvement of endothelial function in diabetic mice. Cell Metab 14:104–115CrossRefPubMedGoogle Scholar
  40. 40.
    Tsang JY, Li D, Ho D, Peng J, Xu A, Lamb J, Chen Y, Tam PK (2011) Novel immunomodulatory effects of adiponectin on dendritic cell functions. Int Immunopharmacol 11:604–609CrossRefPubMedGoogle Scholar
  41. 41.
    Yang H, Zhang R, Mu H, Li M, Yao Q, Chen C (2006) Adiponectin promotes endothelial cell differentiation from human peripheral CD14+ monocytes in vitro. J Cell Mol Med 10:459–469CrossRefPubMedGoogle Scholar
  42. 42.
    Ma K, Cabrero A, Saha PK, Kojima H, Li L, Chang BH, Paul A, Chan L (2002) Increased beta-oxidation but no insulin resistance or glucose intolerance in mice lacking adiponectin. J Biol Chem 277:34658–34661CrossRefPubMedGoogle Scholar
  43. 43.
    Aprahamian T, Bonegio RG, Richez C, Yasuda K, Chiang LK, Sato K, Walsh K, Rifkin IR (2009) The peroxisome proliferator-activated receptor gamma agonist rosiglitazone ameliorates murine lupus by induction of adiponectin. J Immunol 182:340–346CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Shibata S, Tada Y, Hau C S, Mitsui A, Kamata M, Asano Y, Sugaya M, Kadono T et al (2015) Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from gamma delta-T cells. Nat Commun 6Google Scholar
  45. 45.
    Soleimani M, Jameie SB, Mehdizadeh M, Keradi M, Masoumipoor M, Mehrabi S (2014) Vitamin D3 influence the Th1/Th2 ratio in C57BL/6 induced model of experimental autoimmune encephalomyelitis. Iran J Basic Med Sci 17:785–792PubMedPubMedCentralGoogle Scholar
  46. 46.
    Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel RA, Weiner HL, Nabavi N, et al. (1995) B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80:707–718CrossRefPubMedGoogle Scholar
  47. 47.
    Murugaiyan G, da Cunha AP, Ajay AK, Joller N, Garo LP, Kumaradevan S, Yosef N, Vaidya VS, et al. (2015) MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest 125:1069–1080CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM (2008) IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 205:1535–1541CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Palmer C, Hampartzoumian T, Lloyd A, Zekry A (2008) A novel role for adiponectin in regulating the immune responses in chronic hepatitis C virus infection. Hepatology 48:374–384CrossRefPubMedGoogle Scholar
  50. 50.
    Dong C (2014) Targeting Th17 cells in immune diseases. Cell Res 24:901–903CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A (2010) Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol 30:328–339CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kai Zhang
    • 1
    • 2
  • Yawei Guo
    • 3
  • Zhenzhen Ge
    • 1
  • Zhihui Zhang
    • 1
  • Yurong Da
    • 1
  • Wen Li
    • 1
  • Zimu Zhang
    • 1
  • Zhenyi Xue
    • 1
  • Yan Li
    • 1
  • Yinghui Ren
    • 1
  • Long Jia
    • 1
  • Koon-Ho Chan
    • 4
  • Fengrui Yang
    • 1
  • Jun Yan
    • 5
  • Zhi Yao
    • 1
  • Aimin Xu
    • 4
  • Rongxin Zhang
    • 1
    • 2
    Email author
  1. 1.Department of Immunology, Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of ChinaTianjin Medical UniversityTianjinChina
  2. 2.Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of EndocrinologyTianjin Medical UniversityTianjinChina
  3. 3.Department of Family Medicine and Primary Care, Department of MedicineThe University of Hong KongHong KongChina
  4. 4.State Key laboratory of Pharmaceutical Biotechnology, and Department of MedicineThe University of Hong KongHong KongChina
  5. 5.Tianjin Animal Science and Veterinary Research InstituteTianjinChina

Personalised recommendations