DISCOVERIES (ISSN 2359-7232), 2013, October-December

CITATION:
Raval FM, Nikolajczyk BS. The Bidirectional Relationship between Metabolism and Immune Responses. Discoveries 2013, Oct-Dec; 1(1): e6.
DOI: 10.15190/d.2013.6

Submitted: November 25, 2013; Revised: December 30, 2013; Accepted: December 30, 2013; Published: December 31, 2013; 

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The Bidirectional Relationship between Metabolism and Immune Responses

Forum M. Raval and Barbara S. Nikolajczyk*

Affiliation:
Boston University School of Medicine, Department of Microbiology, Boston, MA, USA

*Correspondence to: Prof. Barbara S. Nikolajczyk, Department of Microbiology, Boston University School of Medicine; Phone: 617-638-7019; Fax: 617-638-4286; Email: bnikol@bu.edu

Abstract

Immunometabolism investigates the multiple links between the immune system and metabolism. One main focus of immunometabolism investigates how obesity impacts the immune system and pro-inflammatory immune cell function, leading to metabolic diseases, including type 2 diabetes (T2D). The second focus stresses the metabolic changes that dictate immune cell activation. Several groups have studied these two arms of the field individually, but work that integrates both topics will be required to develop an accurate understanding of how immune cells and metabolic pathways collaborate in obesity and obesity-associated T2D. Investigations of the relationships among obesity-induced changes in the nutritional environment, immune cell activation, and immune cell metabolism may lead to novel and efficacious therapies for obesity-associated disorders such as insulin resistance (IR) and T2D. This review outlines recent insights into two related processes: 1. the role that energy utilization plays in immune responses and 2. the immune cell functions that drive obesity and T2D. Herein, we begin to consider how shifts in available fuel sources in obesity and T2D impact the immune response to both pathogens and chronic over nutrition.

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Acknowledgements

This work was supported by NIH grant R56 DK096525 (to BSN).

References

1. Nikolajczyk, B.S., Jagannathan-Bogdan, M., Denis, G.V. The outliers become a stampede as immuno-metabolism reaches a tipping point. Immunol. Rev. 2012; 249: 253-275.
2. DeFuria, J. et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 5133–5138.
3. Jagannathan-Bogdan, M. et al. Elevated pro-inflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J. Immunol. 2011; 186: 1162–1172.
4. Olefsky, J. M. & Glass, C. K. Macrophages, Inflammation, and Insulin Resistance. Annu. Rev. Physiol. 2010; 72: 219-46.
5. Da Young Oh, Morinaga, H., Talukdar, S., Bae, E. J. & Olefsky, J. M. Increased Macrophage Migration Into Adipose Tissue in Obese Mice. Diabetes 2012; 61: 346-354.
6. Orr, J. S. et al. Obesity Alters Adipose Tissue Macrophage Iron Content and Tissue Iron Distribution. Diabetes 2013.
7. Shu, C. J., Christophe Benoist & Diane Mathis. The immune system’s involvement in obesity-driven type 2 diabetes. Semin Immunol. 2013.
8. Jagannathan, M. et al. Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 2010; 53: 1461–1471.
9. Winer, D. A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 2011; 17: 610–617.
10. Ioan-Facsinay, A. et al. Adipocyte-derived lipids modulate CD4+ T-cell function. Eur. J. Immunol. 2013; 43: 1578-1587.
11. Murano, I. et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J. Lipid Res. 2008; 49: 1562–1568.
12. Wu, H. et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 2007; 115: 1029–1038.
13. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine 2009; 15: 914-920.
14. Yang, H. et al. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J. Immunol. 2010; 185: 1836–1845.
15. O'Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010; 327; 1098–1102.
16. Goossens, G. H. et al. Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans. Mol. Immunol. 2012; 50: 142–149.
17. Haskell, B. D., Flurkey, K., Duffy, T. M., Sargent, E. E. & Leiter, E. H. The Diabetes-Prone NZO/HlLt Strain. I. Immunophenotypic Comparison to the Related NZB/BlNJ and NZW/LacJ Strains. Laboratory Investigation 2002; 82: 833–842.
18. Gotoh, K. et al. A Novel Anti-inflammatory Role for Spleen-Derived Interleukin-10 in Obesity-Induced Inflammation in White Adipose Tissue and Liver. Diabetes 2012; 61: 1994-2003.
19. Nishimura, S. et al. Adipose Natural Regulatory B Cells Negatively Control Adipose Tissue Inflammation. Cell Metab. 2013; 18: 759-766.
20. Kuniko Takagi et al. Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans. Nature Communication 2013.
21. Jagannathan, M. et al. TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients. J. Immunol. 2009; 183: 7461–7470.
22. Fox, C. J., Hammerman, P. S. & Thompson, C. B. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 2005; 5: 844–852.
23. Pearce, E. L. & Pearce, E. J. Metabolic Pathways in Immune Cell Activation and Quiescence. Immunity 2013; 38: 633-643.
24. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029–1033.
25. Hammerman, P. S., Fox, C. J. & Thompson, C. B. Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends Biochem. Sci. 2004; 29: 586–592.
26. SanshiroTateya, Kim, F. & Tamori, A. Y. Recent advances in obesity-induced inflammation and insulin resistance. Frontiers in Endrocrin. 2013; 4: 1-14.
27. Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460: 103–107.
28. Michalek, R. D. et al. Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets. J Immunol. 2011; 186: 3299-3303.
29. Hardie, L. A. J. O. D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature Rev. 2013; 493: 346-355 (2013).
30. Gauthier, M.-S. et al. Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans. Biochem. Biophys. Res. Commun. 2011; 404: 382–387.
31. Frauwirth, K. A. & Thompson, C. B. Regulation of T Lymphocyte Metabolism. J Immunol. 2004; 172: 4661-4665.
32. Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010; 115: 4742–4749.
33. Rodríguez-Prados, J.-C. et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 2010; 185: 605–614.
34. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1ß through HIF-1a. Nature 2013; 496: 238–242.
35. Doughty, C. A. et al. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 2006; 107: 4458-4465.
36. Dufort, F. J. et al. Cutting edge: IL-4-mediated protection of primary B lymphocytes from apoptosis via Stat6-dependent regulation of glycolytic metabolism. The Journal of Immunology 2007; 179: 4953–4957.
37. Woodland, R. T. et al. Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival. Blood 2008; 111: 750–760.
38. Shi, H. et al. TLR4 links innate immunity and fatty acid–induced insulin resistance. Journal of Clin. Invest. 2006; 116: 3015-3025.
39. Weigert, C. et al. Mechanisms of Signal Transduction:Palmitate, but Not Unsaturated Fatty Acids, Induces the Expression of Interleukin-6 in Human Myotubes through Proteasome-dependent Activation of Nuclear Factor-?B. J. Biol. Chem. 2004; 279: 23942-23952.
40. Figueras, M., Olivan, M., Busquets, S., López-Soriano, F. J. & Argilés, J. M. Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status. Obesity (Silver Spring) 2011; 19: 362–369.
41. Yazdani-Biuki, B. et al. Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. Eur. J. Clin. Invest. 2004 ; 34 : 641–642.
42. Larsen, C. M. et al. Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus. N Engl J Med 2007; 356: 1517–1526.
43. Goldfine, A. B. et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci 2008; 1: 36–43.
44. Koska, J. et al. The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia 2009; 52: 385–393.
45. Sakamoto, G. R. E. R. P. K. Molecular mechanism of action of metformin: old or new insights? Diabetologia 2013; 56: 1898-1906.
46. Leung, J. et al. Possible Association between Obesity and Clostridium difficile Infection. Emerging Infect. Dis. 2013; 19: 1791–1798.

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