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OX40 promotes obesity-induced adipose inflammation and insulin resistance

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Abstract

Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4+ T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation. The effects of OX40 on IR are mechanistically linked to the promotion of T cell activation, Th1 cell differentiation and proliferation—as well as the attenuation of Treg suppressive activity and the enhancement of proinflammatory cytokine production—in adipose tissues. Furthermore, OX40 expression on T cells was positively associated with obesity in humans, suggesting that our findings are clinically relevant. In summary, our study revealed that OX40 in CD4+ T cells is crucial for adipose tissue inflammation and IR development. Therefore, the OX40 signaling pathway may be a new target for preventing or treating obesity-related IR and T2DM.

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Abbreviations

APC:

Antigen presenting cell

DIO:

Diet-induced obesity

EdU:

5-Ethynyl-2′-deoxyuridine

FACS:

Fluorescence-activated cell sorting

Foxp3:

Transcription factor forkhead box P3

Gata3:

Transcription factor GATA binding protein 3

GTT:

Glucose tolerance test

HBSS:

Hanks’ balanced salt solution

HE:

Hematoxylin–eosin

HFD:

High-fat diet

IL-2:

Interleukin 2

IL-4:

Interleukin 4

IL-6:

Interleukin 6

IL-10:

Interleukin 10

IL-17a:

Interleukin 17a

IFN-γ:

Interferon-γ

IR:

Insulin resistance

ITT:

Insulin tolerance test

KO:

Knockout

mAb:

Monoclonal antibody

MHC-II:

MHC class II

NCD:

Normal control diet

NKT:

Natural killer T cells

PBMC:

Peripheral blood mononuclear cell

T2DM:

Type 2 diabetes mellitus

Tbx21:

T-box transcription factor TBX21

Th1:

T helper 1

TNF-α:

Tumor necrosis factor alpha

Tregs:

T regulatory cells

VAT:

Visceral adipose tissue

WT:

Wide type

References

  1. Mathis D (2013) Immunological goings-on in visceral adipose tissue. Cell Metab 17(6):851–859. doi:10.1016/j.cmet.2013.05.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kalupahana NS, Moustaid-Moussa N, Claycombe KJ (2012) Immunity as a link between obesity and insulin resistance. Mol Aspects Med 33(1):26–34. doi:10.1016/j.mam.2011.10.011

    Article  CAS  PubMed  Google Scholar 

  3. Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11(2):85–97. doi:10.1038/nri2921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445. doi:10.1146/annurev-immunol-031210-101322

    Article  CAS  PubMed  Google Scholar 

  5. Cildir G, Akincilar SC, Tergaonkar V (2013) Chronic adipose tissue inflammation: all immune cells on the stage. Trends Mol Med 19(8):487–500. doi:10.1016/j.molmed.2013.05.001

    Article  CAS  PubMed  Google Scholar 

  6. McNelis JC, Olefsky JM (2014) Macrophages, immunity, and metabolic disease. Immunity 41(1):36–48. doi:10.1016/j.immuni.2014.05.010

    Article  CAS  PubMed  Google Scholar 

  7. Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, Fischer-Posovszky P, Barth TF, Dragun D, Skurk T, Hauner H, Bluher M, Unger T, Wolf AM, Knippschild U, Hombach V, Marx N (2008) T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol 28(7):1304–1310. doi:10.1161/ATVBAHA.108.165100

    Article  CAS  PubMed  Google Scholar 

  8. Lee BC (1842) Lee J (2014) Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 3:446–462. doi:10.1016/j.bbadis.2013.05.017

    Google Scholar 

  9. Seijkens T, Kusters P, Chatzigeorgiou A, Chavakis T, Lutgens E (2014) Immune cell crosstalk in obesity: a key role for costimulation? Diabetes 63(12):3982–3991. doi:10.2337/db14-0272

    Article  CAS  PubMed  Google Scholar 

  10. Deng T, Lyon CJ, Minze LJ, Lin J, Zou J, Liu JZ, Ren Y, Yin Z, Hamilton DJ, Reardon PR, Sherman V, Wang HY, Phillips KJ, Webb P, Wong ST, Wang RF, Hsueh WA (2013) Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 17(3):411–422. doi:10.1016/j.cmet.2013.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15(8):921–929. doi:10.1038/nm.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, Blin-Wakkach C, Anty R, Iannelli A, Gugenheim J, Tran A, Bouloumie A, Gual P, Wakkach A (2012) Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61(9):2238–2247. doi:10.2337/db11-1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morris DL, Cho KW, Delproposto JL, Oatmen KE, Geletka LM, Martinez-Santibanez G, Singer K, Lumeng CN (2013) Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes 62(8):2762–2772. doi:10.2337/db12-1404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wu H, Perrard XD, Wang Q, Perrard JL, Polsani VR, Jones PH, Smith CW, Ballantyne CM (2010) CD11c expression in adipose tissue and blood and its role in diet-induced obesity. Arterioscler Thromb Vasc Biol 30(2):186–192. doi:10.1161/ATVBAHA.109.198044

    Article  CAS  PubMed  Google Scholar 

  15. Cho KW, Morris DL, DelProposto JL, Geletka L, Zamarron B, Martinez-Santibanez G, Meyer KA, Singer K, O’Rourke RW, Lumeng CN (2014) An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Rep 9(2):605–617. doi:10.1016/j.celrep.2014.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13(4):227–242. doi:10.1038/nri3405

    Article  PubMed  PubMed Central  Google Scholar 

  17. Croft M (2010) Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol 28:57–78. doi:10.1146/annurev-immunol-030409-101243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246. doi:10.1146/annurev-physiol-021909-135846

    Article  CAS  PubMed  Google Scholar 

  19. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394(6696):897–901. doi:10.1038/29795

    Article  CAS  PubMed  Google Scholar 

  20. Sell H, Habich C, Eckel J (2012) Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 8(12):709–716. doi:10.1038/nrendo.2012.114

    Article  CAS  PubMed  Google Scholar 

  21. Chng MH, Alonso MN, Barnes SE, Nguyen KD, Engleman EG (2015) Adaptive immunity and antigen-specific activation in obesity-associated insulin resistance. Mediat Inflamm 2015:593075. doi:10.1155/2015/593075

    Article  Google Scholar 

  22. Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M (2000) The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol 165(6):3043–3050

    Article  CAS  PubMed  Google Scholar 

  23. Bansal-Pakala P, Halteman BS, Cheng MH, Croft M (2004) Costimulation of CD8 T cell responses by OX40. J Immunol 172(8):4821–4825

    Article  CAS  PubMed  Google Scholar 

  24. Lee SW, Park Y, Song A, Cheroutre H, Kwon BS, Croft M (2006) Functional dichotomy between OX40 and 4-1BB in modulating effector CD8 T cell responses. J Immunol 177(7):4464–4472

    Article  CAS  PubMed  Google Scholar 

  25. Croft M, So T, Duan W, Soroosh P (2009) The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev 229(1):173–191. doi:10.1111/j.1600-065X.2009.00766.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ward-Kavanagh LK, Lin WW, Sedy JR, Ware CF (2016) The TNF receptor superfamily in co-stimulating and co-inhibitory responses. Immunity 44(5):1005–1019. doi:10.1016/j.immuni.2016.04.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kaur D, Brightling C (2012) OX40/OX40 ligand interactions in T-cell regulation and asthma. Chest 141(2):494–499. doi:10.1378/chest.11-1730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cipolletta D, Kolodin D, Benoist C, Mathis D (2011) Tissular T(regs): a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin Immunol 23(6):431–437. doi:10.1016/j.smim.2011.06.002

    Article  CAS  PubMed  Google Scholar 

  29. Winer S, Winer DA (2012) The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance. Immunol Cell Biol 90(8):755–762. doi:10.1038/icb.2011.110

    Article  CAS  PubMed  Google Scholar 

  30. Bour-Jordan H, Bluestone JA (2009) Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells. Immunol Rev 229(1):41–66. doi:10.1111/j.1600-065X.2009.00775.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhong J, Rao X, Braunstein Z, Taylor A, Narula V, Hazey J, Mikami D, Needleman B, Rutsky J, Sun Q, Deiuliis JA, Satoskar AR, Rajagopalan S (2014) T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes 63(4):1289–1302. doi:10.2337/db13-1094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wolf D, Jehle F, Michel NA, Bukosza EN, Rivera J, Chen YC, Hoppe N, Dufner B, Rodriguez AO, Colberg C, Nieto L, Rupprecht B, Wiedemann A, Schulte L, Peikert A, Bassler N, Lozhkin A, Hergeth SP, Stachon P, Hilgendorf I, Willecke F, von Zur Muhlen C, von Elverfeldt D, Binder CJ, Aichele P, Varo N, Febbraio MA, Libby P, Bode C, Peter K, Zirlik A (2014) Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice. Circulation 129(23):2414–2425. doi:10.1161/CIRCULATIONAHA.113.008055

    Article  CAS  PubMed  Google Scholar 

  33. Yi Z, Bishop GA (2015) Regulatory role of CD40 in obesity-induced insulin resistance. Adipocyte 4(1):65–69. doi:10.4161/adip.32214

    Article  CAS  PubMed  Google Scholar 

  34. Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Li XC (2007) OX40 costimulation turns off Foxp3+ Tregs. Blood 110(7):2501–2510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xiao X, Gong W, Demirci G, Liu W, Spoerl S, Chu X, Bishop DK, Turka LA, Li XC (2012) New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol 188(2):892–901. doi:10.4049/jimmunol.1101373

    Article  CAS  PubMed  Google Scholar 

  36. Bai Y, Sun Q (2015) Macrophage recruitment in obese adipose tissue. Obes Rev 16(2):127–136. doi:10.1111/obr.12242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chung KJ, Chatzigeorgiou A, Economopoulou M, Garcia-Martin R, Alexaki VI, Mitroulis I, Nati M, Gebler J, Ziemssen T, Goelz SE, Phieler J, Lim JH, Karalis KP, Papayannopoulou T, Bluher M, Hajishengallis G, Chavakis T (2017) A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat Immunol 18(6):654–664. doi:10.1038/ni.3728

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Grants from the National Natural Science Foundation of China (No. 81500598 and 81501379), Beijing Natural Science Foundation (No. 7162051, 7172060), Beijing Health System Talents Plan (2013-2-026), and the Open Project of Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation (2015YZNS04).

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Author notes

  1. Bing Liu, Hengchi Yu and Guangyong Sun contributed equally to this work.

Authors and Affiliations

  1. Endocrinology Department, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China

    Bing Liu, Hengchi Yu, Jie Yin & Xu Hong

  2. Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong-an Road, Xi-cheng District, Beijing, 100050, People’s Republic of China

    Bing Liu, Hengchi Yu, Guangyong Sun, Xiaojing Sun, Hua Jin, Chunpan Zhang, Wen Shi, Dan Tian, Kai Liu, Hufeng Xu, Xinmin Li & Dong Zhang

  3. Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 100050, People’s Republic of China

    Bing Liu, Hengchi Yu, Guangyong Sun, Xiaojing Sun, Hua Jin, Chunpan Zhang, Wen Shi, Dan Tian, Kai Liu, Hufeng Xu, Xinmin Li & Dong Zhang

  4. Beijing Clinical Research Institute, Beijing, 100050, People’s Republic of China

    Guangyong Sun, Xiaojing Sun, Hua Jin, Chunpan Zhang, Wen Shi, Dan Tian, Kai Liu, Hufeng Xu, Xinmin Li & Dong Zhang

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  1. Bing Liu
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Contributions

BL, HY and GS participated in performing the research, analyzing the data and initiating the original draft of the article. XS, HJ, CZ, DT, WS, KL, HX, XL and JY participated in performing the research and collecting the data. DZ and XH established the hypotheses, supervised the studies, analyzed the data and co-wrote the manuscript.

Corresponding authors

Correspondence to Xu Hong or Dong Zhang.

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There is no conflict of interests to be declared from all authors.

Electronic supplementary material

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18_2017_2552_MOESM1_ESM.tif

Supplementary Figure 1. The gating strategy for flow cytometry. Representative flow cytometry image of gating strategy used for flow cytometry analysis (TIFF 351 kb)

18_2017_2552_MOESM2_ESM.tif

Supplementary Figure 2. OX40 upregulation in T cells promotes DIO and IR. B6.Rag2/Il2rg double knock mice were selectively repopulated with purified CD3 T cells from WT or OX40-KO mice. After 16 weeks HFD feeding, the body weight and plasma fasting glucose levels were measured (n=5 in each group) (TIFF 108 kb)

18_2017_2552_MOESM3_ESM.tif

Supplementary Figure 3. OX40 deficiency suppressed CD4 + T cell activation and differentiation. The percentages of CD44+ cells relative to the total numbers of CD3+, CD4+ and CD8+ T cells were determined by flow cytometry in the indicated groups (n=5 in each group) (A). Absolute number of Th1 (CD4+ IFN-γ+ cells) and Treg (CD4+ Foxp3+ cells) in the adipose tissue and spleen of mice from each group (B). Flow cytometry analysis of CD4+ IL-4+ cells and CD4+ IL-17+ cells relative to the total numbers of CD4+ T cells in the adipose tissue and spleen of mice from each group, expressed as lymphocyte percentages (C) (TIFF 905 kb)

Supplementary material 4 (DOCX 29 kb)

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Liu, B., Yu, H., Sun, G. et al. OX40 promotes obesity-induced adipose inflammation and insulin resistance. Cell. Mol. Life Sci. 74, 3827–3840 (2017). https://doi.org/10.1007/s00018-017-2552-7

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  • DOI: https://doi.org/10.1007/s00018-017-2552-7

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