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The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance

Abstract

The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.

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Figure 1: Reduction of Nlrp3 and IL-1β expression is associated with improvement of insulin sensitivity.
Figure 2: Elimination of Nlrp3 expression prevents obesity-induced caspase-1 cleavage and IL-1β and IL-18 activation.
Figure 3: The Nlrp3 inflammasome regulates insulin sensitivity and steatohepatitis in obesity.
Figure 4: Nlrp3 senses ceramide to induce IL-1β and regulates adipose tissue macrophage activation in obesity.
Figure 5: Ablation of the Nlrp3 inflammasome reduces adipose tissue effector T cells without affecting Treg cells in visceral fat of obese mice.
Figure 6: Elimination of the Nlrp3 inflammasome reduces obesity-induced macrophage–mediated T cell activation in adipose tissue.

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References

  1. Dixit, V.D. Adipose-immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span. J. Leukoc. Biol. 84, 882–892 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hotamisligil, G.S. & Erbay, E. Nutrient sensing and inflammation in metabolic diseases. Nat. Rev. Immunol. 8, 923–934 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Luchsinger, J.A. & Gustafson, D.R. Adiposity, type 2 diabetes and Alzheimer's disease. J. Alzheimers Dis. 16, 693–704 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yang, H. et al. Obesity accelerates thymic aging. Blood 114, 3803–3812 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Odegaard, J.I. & Chawla, A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat. Clin. Pract. Endocrinol. Metab. 4, 619–626 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Patsouris, D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301–309 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Arkan, M.C. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nat. Med. 11, 191–198 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Jager, J., Grémeaux, T., Cormont, M., Le Marchand-Brustel, Y. & Tanti, J.F. Interleukin-1β–induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 148, 241–251 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Larsen, C.M. et al. Interleukin-1–receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Osborn, O. et al. Treatment with an Interleukin 1 β antibody improves glycemic control in diet-induced obesity. Cytokine 44, 141–148 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Barton, G.M. & Kagan, J.C. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat. Rev. Immunol. 9, 535–542 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Agostini, L. et al. NLRP3 forms an IL-1β–processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Lamkanfi, M. & Dixit, V.M. Inflammasomes: guardians of cytosolic sanctity. Immunol. Rev. 227, 95–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Franchi, L., Eigenbrod, T., Muñoz-Planillo, R. & Nuñez, G. The inflammasome: a caspase-1–activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10, 241–247 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Dinarello, C.A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Kostura, M.J. et al. Identification of a monocyte specific pre–interleukin 1 β convertase activity. Proc. Natl. Acad. Sci. USA 86, 5227–5231 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 267, 2000–2003 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Dostert, C. et al. Innate immune activation through Nlrp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Halle, A. et al. The NLRP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NLRP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Shi, H. et al. TLR4 links innate immunity and fatty acid–induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Saberi, M. et al. Hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 10, 419–429 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stienstra, R. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell. Metab. 12, 593–605 (2009).

    Article  Google Scholar 

  33. Bishop, N.A. & Guarente, L. Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat. Rev. Genet. 8, 835–844 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Galgani, J.E. et al. Metabolic flexibility in response to glucose is not impaired in people with type 2 diabetes after controlling for glucose disposal rate. Diabetes 57, 841–845 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Kummer, J.A. et al. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site–specific role in the inflammatory response. J. Histochem. Cytochem. 55, 443–452 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Joosten, L.A. Inflammatory arthritis in caspase 1 gene–deficient mice: contribution of proteinase 3 to caspase 1–independent production of bioactive interleukin-1 β. Arthritis Rheum. 60, 3651–3662 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Virkamäki, A., Ueki, K. & Kahn, C.R. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J. Clin. Invest. 103, 931–943 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Imaeda, A.B. et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nlrp3 inflammasome. J. Clin. Invest. 119, 305–314 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Watanabe, A. et al. Inflammasome-mediated regulation of hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1248–G1257 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Håversen, L., Danielsson, K.N., Fogelstrand, L. & Wiklund, O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis 202, 382–393 (2009).

    Article  PubMed  Google Scholar 

  42. Park, T.S. et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J. Lipid Res. 49, 2101–2112 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Prieur, X., Roszer, T. & Ricote, M. Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome. Biochim. Biophys. Acta 1801, 327–337 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Shah, C. et al. Protection from high fat diet-induced increase in ceramide in mice lacking plasminogen activator inhibitor 1. J. Biol. Chem. 283, 13538–13548 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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. 185, 1836–1845 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. McGonagle, D. & McDermott, M.F. A proposed classification of the immunological diseases. PLoS Med. 3, e297 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, H., Ambade, A. & Re, F. Cutting edge: Necrosis activates the NLRP3 inflammasome. J. Immunol. 183, 1528–1532 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Halberg, N. et al. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 29, 4467–4483 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Strissel, K.J. et al. Adipocyte death, adipose tissue remodeling and obesity complications. Diabetes 56, 2910–2918 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. So, A. & Thorens, B. Uric acid transport and disease. J. Clin. Invest. 120, 1791–1799 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Feig, D.I., Kang, D.H. & Johnson, R.J. Uric acid and cardiovascular risk. N. Engl. J. Med. 359, 1811–1821 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Strissel, K.J. et al. T-cell recruitment and TH1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity 18, 1918–1925 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Duffaut, C. et al. Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators. Arterioscler. Thromb. Vasc. Biol. 29, 1608–1614 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Dominguez, H. et al. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J. Vasc. Res. 42, 517–525 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Lamkanfi, M. et al. Glyburide inhibits the Cryopyrin/Nlrp3 inflammasome. J. Cell Biol. 187, 61–70 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Vishva M. Dixit at Genentech for providing caspase-1–specific antibody and Nlrp3−/− mice and J. Suttles from the University of Louisville for L929 media. We also thank S. Bond for expert technical assistance and D.H. Ryan, C. Bouchard and J.M. Salbaum for helpful discussions. This work was supported in part by pilot grants to B.V. and V.D.D. from the Nutrition and Obesity Research Center (US National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases grant P30 DK072476). The research in the Dixit laboratory is supported in part by the NIH (R01AG31797), the Coypu Foundation and the Pennington Biomedical Research Foundation. K.S. was partially supported by the NIH (DK083615). This work used the facilities of the Genomics and Cell Biology & Bioimaging Core supported by NIH grant 1 P20 RR02/1945.

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B.V. performed real-time PCRs, flow cytometry assays, adipose tissue macrophage selections, some western blots, ITT, GTT and cytokine assays, managed the transgenic animal colony and participated in experimental design, data analysis and manuscript preparation. Y.-H.Y. performed all caspase-1 and IL1β western blots, adipose and liver histologies, and macrophage culture experiments and analyzed the data. A.R. Performed body composition analysis, tissue collections, lipid analysis, animal husbandry, genotyping, ITT, GTT and adipocyte size measurement. J.E.G. and E.R. designed and supervised the human studies, analyzed the glucose and insulin sensitivity data in obese T2DM subjects and discussed the hypotheses. K.S. performed the caspase-1 western blot in the kidneys of HFD fed WT and Nlrp3 null mice. R.L.M. participated in standardizing the ITT and GTT assays and advised on the design of experiments for liver fatty acid synthesis and oxidation gene expression. J.M.S. performed the western blots for some of the insulin-signaling experiments, helped with data interpretation, discussed the hypotheses and participated in manuscript preparation. V.D.D. conceived the project, designed the experiments, performed some of the cytokine assays and flow cytometry, helped with data interpretation, participated in data analysis, directed the project and wrote the manuscript.

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Correspondence to Vishwa Deep Dixit.

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Vandanmagsar, B., Youm, YH., Ravussin, A. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17, 179–188 (2011). https://doi.org/10.1038/nm.2279

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