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Adipocyte and Cell Biology

MRP14 enhances the ability of macrophage to recruit T cells and promotes obesity-induced insulin resistance

International Journal of Obesity (2019) | Download Citation



Myeloid-related protein-14 (MRP14) and its binding partner MRP8 play an essential role in innate immune function and have been implicated in a variety of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage-mediated adipose tissue inflammation and obesity-induced insulin resistance.

Subjects and results

Wild-type (WT) and Mrp14−/− mice were fed with a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese WT mice expressed higher levels of MRP14 in the visceral adipose fat and liver compared with the lean mice. Mrp14−/− mice demonstrated a significantly improved postprandial insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance testing. Macrophages secreted MRP14 in response to inflammatory stimuli, such as LPS. Extracellular MRP8/14 induced the production of CCL5 and CXCL9. Deficiency of MRP14 did not affect macrophage proliferation, mitochondrial respiration, and glycolytic function, but Mrp14−/− macrophages showed a reduced ability to attract T cells. Depletion of the extracellular MRP14 reduced the T cell attracting ability of WT macrophages to a level similar to Mrp14−/− macrophages.


Our data indicate that MRP14 deficiency decreases obesity-induced insulin resistance and MRP8/14 regulates T-cell recruitment through the induction of T-cell chemoattractant production from macrophages.

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  1. 1.

    Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Yamamoto H, et al. The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis. Arthritis Res Ther. 2006;8:R69.

  2. 2.

    Shimizu K, Libby P, Rocha VZ, Folco EJ, Shubiki R, Grabie N, et al. Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection. Circulation. 2011;124:2920–32.

  3. 3.

    Hsu K, Champaiboon C, Guenther BD, Sorenson BS, Khammanivong A, Ross KF, et al. Anti-Infective protective properties of S100 calgranulins. Antiinflamm Antiallergy Agents Med Chem. 2009;8:290–305.

  4. 4.

    Manitz MP, Horst B, Seeliger S, Strey A, Skryabin BV, Gunzer M, et al. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol Cell Biol. 2003;23:1034–43.

  5. 5.

    Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, et al. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med. 2007;13:1042–9.

  6. 6.

    Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem. 1997;272:9496–502.

  7. 7.

    Gross SR, Sin CG, Barraclough R, Rudland PS. Joining S100 proteins and migration: for better or for worse, in sickness and in health. Cell Mol Life Sci. 2014;71:1551–79.

  8. 8.

    Sorci G, Riuzzi F, Giambanco I, Donato R. RAGE in tissue homeostasis, repair and regeneration. Biochim Biophys Acta. 2013;1833:101–9.

  9. 9.

    Turovskaya O, Foell D, Sinha P, Vogl T, Newlin R, Nayak J, et al. RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis. 2008;29:2035–43.

  10. 10.

    Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, et al. S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol. 2008;83:1484–92.

  11. 11.

    Gebhardt C, Riehl A, Durchdewald M, Nemeth J, Furstenberger G, Muller-Decker K, et al. RAGE signaling sustains inflammation and promotes tumor development. J Exp Med. 2008;205:275–85.

  12. 12.

    Croce K, Gao H, Wang Y, Mooroka T, Sakuma M, Shi C, et al. Myeloid-related protein-8/14 is critical for the biological response to vascular injury. Circulation. 2009;120:427–36.

  13. 13.

    Catalan V, Gomez-Ambrosi J, Rodriguez A, Ramirez B, Rotellar F, Valenti V, et al. Increased levels of calprotectin in obesity are related to macrophage content: impact on inflammation and effect of weight loss. Mol Med. 2011;17:1157–67.

  14. 14.

    Mortensen OH, Nielsen AR, Erikstrup C, Plomgaard P, Fischer CP, Krogh-Madsen R, et al. Calprotectin—a novel marker of obesity. PLoS ONE. 2009;4:e7419.

  15. 15.

    Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014;19:821–35.

  16. 16.

    Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17:695–708.

  17. 17.

    Hobbs JA, May R, Tanousis K, McNeill E, Mathies M, Gebhardt C, et al. Myeloid cell function in MRP-14 (S100A9) null mice. Mol Cell Biol. 2003;23:2564–76.

  18. 18.

    Grunewald M, Johnson S, Lu D, Wang Z, Lomberk G, Albert PR, et al. Mechanistic role for a novel glucocorticoid-KLF11 (TIEG2) protein pathway in stress-induced monoamine oxidase A expression. J Biol Chem. 2012;287:24195–206.

  19. 19.

    Xia C, Braunstein Z, Toomey AC, Zhong J, Rao X. S100 Proteins As an Important Regulator of Macrophage Inflammation. Front Immunol. 2017;8:1908.

  20. 20.

    Ma LP, Haugen E, Ikemoto M, Fujita M, Terasaki F, Fu M. S100A8/A9 complex as a new biomarker in prediction of mortality in elderly patients with severe heart failure. Int J Cardiol. 2012;155:26–32.

  21. 21.

    Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot JD, et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell. 2016;166:1512–25. e12.

  22. 22.

    Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18:363–74.

  23. 23.

    Park MH, Kim DH, Lee EK, Kim ND, Im DS, Lee J, et al. Age-related inflammation and insulin resistance: a review of their intricate interdependency. Arch Pharm Res. 2014;37:1507–14.

  24. 24.

    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.

  25. 25.

    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.

  26. 26.

    Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, Edge JA, et al. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19:146–54.

  27. 27.

    Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem. 2006;281:26602–14.

  28. 28.

    Asakura M, Karaki F, Fujii H, Atsuda K, Itoh T, Fujiwara R. Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. Sci Rep. 2016;6:35633.

  29. 29.

    Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17:179–88.

  30. 30.

    Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–9.

  31. 31.

    Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, et al. beta-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep. 2017;18:2077–87.

  32. 32.

    Anderson EK, Gutierrez DA, Hasty AH. Adipose tissue recruitment of leukocytes. Curr Opin Lipidol. 2010;21:172–7.

  33. 33.

    Carvalheira JB, Qiu Y, Chawla A. Blood spotlight on leukocytes and obesity. Blood. 2013;122:3263–7.

  34. 34.

    Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities Study): a cohort study. Lancet. 1999;353:1649–52.

  35. 35.

    Kawano Y, Nakae J, Watanabe N, Kikuchi T, Tateya S, Tamori Y, et al. Colonic pro-inflammatory macrophages cause insulin resistance in an intestinal Ccl2/Ccr2-dependent manner. Cell Metab. 2016;24:295–310.

  36. 36.

    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

  37. 37.

    Olson TS, Ley K. Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integr Comp Physiol. 2002;283:R7–28.

  38. 38.

    Galvan-Pena S, O’Neill LA. Metabolic reprograming in macrophage polarization. Front Immunol. 2014;5:420.

  39. 39.

    Bustos R, Sobrino F. Stimulation of glycolysis as an activation signal in rat peritoneal macrophages. Effect of glucocorticoids on this process. Biochem J. 1992;282(Pt 1):299–303.

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This work was supported by grants from National Institutes of Health (K01DK105108 and K99ES026241), National Natural Science Foundation of China (81670431, 31870906, 81370942, Y2110580, and 81101247), National Science and Technology Major Project (2016YFC1305803), American Heart Association (17GRNT33670485), American Association of Immunologists (CIIF-8745), and Hubei Regenerative Medicine Research Center.

Author information


  1. College of Health Science & Nursing, Wuhan Polytechnic University, 430023, Wuhan, Hubei, China

    • Chang Xia
  2. Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, 44106, USA

    • Chang Xia
    • , Michael Razavi
    • , Yunmei Wang
    • , Daniel I. Simon
    • , Sanjay Rajagopalan
    •  & Jixin Zhong
  3. Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, 97239, USA

    • Xiaoquan Rao
  4. Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA

    • Zachary Braunstein
    •  & Shi Zhao
  5. Department of Endocrinology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430014, Wuhan, Hubei, China

    • Hong Mao
  6. Department of Health Sciences, University of Missouri, Columbia, MO, USA

    • Amelia C. Toomey


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CX and JZ researched data and wrote the paper. XR and ZB researched data. MR, ZB, SZ, DIS, SR, HM, ACT, and XR contributed to discussion. JZ, ZB, MR, ACT, and SZ reviewed and edited the paper. JZ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Shi Zhao or Jixin Zhong.

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