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  • Review Article
  • Published:

Innate immunity in diabetes and diabetic nephropathy

Nature Reviews Nephrology volume 12, pages 13–26 (2016)Cite this article

Subjects

Key Points

  • The innate immune system consists of several classes of pattern recognition receptors, including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response

  • TLR2 and TLR4 are the predominant TLRs expressed on pancreatic β cells which trigger an inflammatory response that results in insulitis during type 1 diabetes mellitus

  • TLR2 and TLR4 signalling, and activation of NLRP3 inflammasomes result in the production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity

  • Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines

  • TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy

  • The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy

Abstract

The innate immune system includes several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL-1β, and IL-18 thereby initiating an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome can induce the production of various proinflammatory cytokines and are critically involved in inflammatory responses in pancreatic islets, and in adipose, liver and kidney tissues. This Review describes how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction resulting in insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways could be beneficial for the treatment of diabetes mellitus and diabetic nephropathy.

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Figure 1: TLRs and signalling molecules.
Figure 2: NLRs.
Figure 3: Innate immunity and inflammatory pathways in diabetic nephropathy and obesity-related kidney diseases.

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References

  1. International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation [online], (2013).

  2. Saran, R. et al. US renal data system 2014 annual data report: epidemiology of kidney disease in the United States. Am. J. Kidney Dis. 66, S1–S306 (2015).

    Article  Google Scholar 

  3. Gaede, P., Lund-Andersen, H., Parving, H. H. & Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580–591 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Wada, J. & Makino, H. Inflammation and the pathogenesis of diabetic nephropathy. Clin. Sci. 124, 139–152 (2013).

    Article  CAS  Google Scholar 

  5. Murphy, K., Travers, P., Walport, M. & Janeway, C. Janeway's Immunobiology 8th edn (Garland Science, 2012).

    Google Scholar 

  6. Mogensen, T. H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240–273 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Dowling, J. K. & O'Neill, L. A. Biochemical regulation of the inflammasome. Crit. Rev. Biochem. Mol. Biol. 47, 424–443 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Leemans, J. C., Kors, L., Anders, H. J. & Florquin, S. Pattern recognition receptors and the inflammasome in kidney disease. Nat. Rev. Nephrol. 10, 398–414 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Anders, H. J. & Muruve, D. A. The inflammasomes in kidney disease. J. Am. Soc. Nephrol. 22, 1007–1018 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Prajapati, B., Jena, P. K., Rajput, P., Purandhar, K. & Seshadri, S. Understanding and modulating the Toll like receptors (TLRs) and NOD like receptors (NLRs) cross talk in type 2 diabetes. Curr. Diabetes Rev. 10, 190–200 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Takeda, K. & Akira, S. Toll-like receptors in innate immunity. Int. Immunol. 17, 1–14 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Godfroy, J. I. 3rd, Roostan, M., Moroz, Y. S., Korendovych, I. V. & Yin, H. Isolated Toll-like receptor transmembrane domains are capable of oligomerization. PLoS ONE 7, e48875 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Janssens, S. & Beyaert, R. Role of Toll-like receptors in pathogen recognition. Clin. Microbiol. Rev. 16, 637–646 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Song, D. H. & Lee, J. O. Sensing of microbial molecular patterns by Toll-like receptors. Immunol. Rev. 250, 216–229 (2012).

    Article  PubMed  CAS  Google Scholar 

  16. Liu, Y., Yin, H., Zhao, M. & Lu, Q. TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin. Rev. Allergy Immunol. 47, 136–147 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. De Nardo, D. Toll-like receptors: activation, signalling and transcriptional modulation. Cytokine 74, 181–189 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Frazão, J. B., Errante, P. R. & Condino-Neto, A. Toll-like receptors' pathway disturbances are associated with increased susceptibility to infections in humans. Arch. Immunol. Ther. Exp. (Warsz.) 61, 427–443 (2013).

    Article  CAS  Google Scholar 

  19. Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Nakamura, N. et al. Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 509, 240–244 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Bertrand, M. J. et al. Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30, 789–801 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Caruso, R., Warner, N., Inohara, N. & Nunez, G. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41, 898–908 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Arend, W. P., Palmer, G. & Gabay, C. IL-1, IL-18, and IL-33 families of cytokines. Immunol. Rev. 223, 20–38 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Zhong, Y., Kinio, A. & Saleh, M. Functions of NOD-like receptors in human diseases. Front. Immunol. 4, 333 (2013).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Bauernfeind, F. & Hornung, V. Of inflammasomes and pathogens—sensing of microbes by the inflammasome. EMBO Mol. Med. 5, 814–826 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Vanaja, S. K., Rathinam, V. A. & Fitzgerald, K. A. Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell Biol. 25, 308–315 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Walker, L. S. & von Herrath, M. CD4 T cell differentiation in type 1 diabetes. Clin. Exp. Immunol. http://dx.doi.org/10.1111/cei.12672.

  30. Zipris, D. Innate immunity and its role in type 1 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 15, 326–331 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Park, Y., Park, S., Yoo, E., Kim, D. & Shin, H. Association of the polymorphism for Toll-like receptor 2 with type 1 diabetes susceptibility. Ann. NY Acad. Sci. 1037, 170–174 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Nussbaum, G., Zanin-Zhorov, A., Quintana, F., Lider, O. & Cohen, I. R. Peptide p277 of HSP60 signals T cells: inhibition of inflammatory chemotaxis. Int. Immunol. 18, 1413–1419 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Karumuthil-Melethil, S. et al. TLR2- and Dectin 1-associated innate immune response modulates T-cell response to pancreatic β-cell antigen and prevents type 1 diabetes. Diabetes 64, 1341–1357 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Karumuthil-Melethil, S., Perez, N., Li, R. & Vasu, C. Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes. J. Immunol. 181, 8323–8334 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Filippi, C. M. et al. TLR2 signaling improves immunoregulation to prevent type 1 diabetes. Eur. J. Immunol. 41, 1399–1409 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Lee, M. S. Treatment of autoimmune diabetes by inhibiting the initial event. Immune Netw. 13, 194–198 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  37. Li, M., Song, L., Gao, X., Chang, W. & Qin, X. Toll-like receptor 4 on islet β cells senses expression changes in high-mobility group BOX 1 and contributes to the initiation of type 1 diabetes. Exp. Mol. Med. 44, 260–267 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Kruger, B. et al. Islet-expressed TLR2 and TLR4 sense injury and mediate early graft failure after transplantation. Eur. J. Immunol. 40, 2914–2924 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Xiao, L., Liu, Y. & Wang, N. New paradigms in inflammatory signaling in vascular endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 306, H317–H325 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Li, J. et al. Enhanced inflammatory responses to toll-like receptor 2/4 stimulation in type 1 diabetic coronary artery endothelial cells: the effect of insulin. Cardiovasc. Diabetol. 9, 90 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Schmidt, L. & Carrillo-Sepulveda, M. A. Toll-like receptor 2 mediates vascular contraction and activates RhoA signaling in vascular smooth muscle cells from STZ-induced type 1 diabetic rats. Pflugers Archiv. http://dx.doi.org/10.1007/s00424-015-1688–2.

  42. Labrum, R., Bevan, S., Sitzer, M., Lorenz, M. & Markus, H. S. Toll receptor polymorphisms and carotid artery intima-media thickness. Stroke 38, 1179–1184 (2007).

    Article  PubMed  Google Scholar 

  43. Liu, F. et al. Frequency of TLR 2, 4, and 9 gene polymorphisms in Chinese population and their susceptibility to type 2 diabetes and coronary artery disease. J. Biomed. Biotechnol. 2012, 373945 (2012).

    PubMed Central  PubMed  Google Scholar 

  44. Martinon, F., Gaide, O., Petrilli, V., Mayor, A. & Tschopp, J. NALP inflammasomes: a central role in innate immunity. Semin. Immunopathol. 29, 213–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Sarkar, S. A. et al. Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor κ-B (NF-κB) signalling in human islets and in a mouse β cell line. Diabetologia 52, 1092–1101 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Moran, A. et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 381, 1905–1915 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Pontillo, A. et al. Two SNPs in NLRP3 gene are involved in the predisposition to type-1 diabetes and celiac disease in a pediatric population from northeast Brazil. Autoimmunity 43, 583–589 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Motta, V. N. et al. Identification of the inflammasome Nlrp1b as the candidate gene conferring diabetes risk at the Idd4.1 locus in the nonobese diabetic mouse. J. Immunol. 194, 5663–5673 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Fresno, M., Alvarez, R. & Cuesta, N. Toll-like receptors, inflammation, metabolism and obesity. Arch. Pysiol. Biochem. 117, 151–164 (2011).

    Article  CAS  Google Scholar 

  50. Tanti, J. F., Ceppo, F., Jager, J. & Berthou, F. Implication of inflammatory signaling pathways in obesity-induced insulin resistance. Front. Endocrinol. 3, 181 (2012).

    Google Scholar 

  51. Apostolopoulos, V. et al. The complex immunological and inflammatory network of adipose tissue in obesity. Mol. Nutr. Food Res. http://dx.doi.org/10.1002/mnfr.201500272.

  52. Himes, R. W. & Smith, C. W. Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J. 24, 731–739 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Davis, J. E., Braucher, D. R., Walker-Daniels, J. & Spurlock, M. E. Absence of Tlr2 protects against high-fat diet-induced inflammation and results in greater insulin-stimulated glucose transport in cultured adipocytes. J. Nutr. Biochem. 22, 136–141 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Kuo, L. H. et al. Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse. Diabetologia 54, 168–179 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Vitseva, O. I. et al. Inducible Toll-like receptor and NF-κB regulatory pathway expression in human adipose tissue. Obesity 16, 932–937 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Murumalla, R. K. et al. Fatty acids do not pay the toll: effect of SFA and PUFA on human adipose tissue and mature adipocytes inflammation. Lipids Health Dis. 11, 175 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Wan, Z., Durrer, C., Mah, D., Simtchouk, S. & Little, J. P. One-week high-fat diet leads to reduced Toll-like receptor 2 expression and function in young healthy men. Nutrition Res. 34, 1045–1051 (2014).

    Article  CAS  Google Scholar 

  58. Hosoi, T., Yokoyama, S., Matsuo, S., Akira, S. & Ozawa, K. Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice. PLoS ONE 5, e12537 (2010).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. Bollyky, P. L. et al. The Toll-like receptor signaling molecule Myd88 contributes to pancreatic β-cell homeostasis in response to injury. PLoS ONE 4, e5063 (2009).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. Caesar, R., Tremaroli, V., Kovatcheva-Datchary, P., Cani, P. D. & Backhed, F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 22, 1–11 (2015).

    Article  CAS  Google Scholar 

  61. Kleinridders, A. et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 10, 249–259 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Alkanani, A. K. et al. Induction of diabetes in the RIP-B7.1 mouse model is critically dependent on TLR3 and MyD88 pathways and is associated with alterations in the intestinal microbiome. Diabetes 63, 619–631 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Everard, A. et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat. Comm. 5, 5648 (2014).

    Article  CAS  Google Scholar 

  64. Balmer, M. L. et al. Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. J. Immunol. 193, 5273–5283 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Schenten, D. et al. Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells. Immunity 40, 78–90 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Velloso, L. A., Folli, F. & Saad, M. J. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocrine Rev. 36, 245–271 (2015).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Tsukumo, D. M. et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 1986–1998 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Suganami, T. et al. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem. Biophys. Res. Comm. 354, 45–49 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Poggi, M. et al. C3H/HeJ mice carrying a Toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50, 1267–1276 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Frisard, M. I. et al. Toll-like receptor 4 modulates skeletal muscle substrate metabolism. Am. J. Physiol. Endocrinol. Metab. 298, E988–E998 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Kim, F. et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ. Res. 100, 1589–1596 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. 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 Central  PubMed  Google Scholar 

  74. Jia, L. et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat. Comm. 5, 3878 (2014).

    Article  CAS  Google Scholar 

  75. Kiely, A., Robinson, A., McClenaghan, N. H., Flatt, P. R. & Newsholme, P. Toll-like receptor agonist induced changes in clonal rat BRIN-BD11 β-cell insulin secretion and signal transduction. J. Endocrinol. 202, 365–373 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Hardy, O. T., Kim, A., Ciccarelli, C., Hayman, L. L. & Wiecha, J. Increased Toll-like receptor (TLR) mRNA expression in monocytes is a feature of metabolic syndrome in adolescents. Pediatr. Obes. 8, e19–e23 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Samuvel, D. J. et al. TLR4 activation and IL-6-mediated cross talk between adipocytes and mononuclear cells synergistically stimulate MMP-1 expression. Endocrinology 152, 4662–4671 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Nativel, B. et al. Soluble HMGB1 is a novel adipokine stimulating IL-6 secretion through RAGE receptor in SW872 preadipocyte cell line: contribution to chronic inflammation in fat tissue. PLoS ONE 8, e76039 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Nagareddy, P. R. et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 19, 821–835 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Hussey, S. E. et al. TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells. Biosci. Rep. 33, 37–47 (2013).

    Article  CAS  Google Scholar 

  82. Caricilli, A. M. et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 9, e1001212 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Kellermayer, R. et al. Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice. FASEB J. 25, 1449–1460 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Kim, K. A., Gu, W., Lee, I. A., Joh, E. H. & Kim, D. H. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE 7, e47713 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Ji, Y. et al. Diet-induced alterations in gut microflora contribute to lethal pulmonary damage in TLR2/TLR4-deficient mice. Cell Rep. 8, 137–149 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Pekkala, S. et al. Toll-like receptor 5 in obesity: the role of gut microbiota and adipose tissue inflammation. Obesity 23, 581–590 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Leichtle, A. et al. TLR4-mediated induction of TLR2 signaling is critical in the pathogenesis and resolution of otitis media. Innate Immun. 15, 205–215 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Coope, A. et al. Chaperone insufficiency links TLR4 protein signaling to endoplasmic reticulum stress. J. Biol. Chem. 287, 15580–15589 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Okla, M. et al. Activation of Toll-like receptor (TLR) 4 attenuates adaptive thermogenesis via endoplasmic reticulum stress. J. Biol. Chem. http://dx.doi.org/10.1074/jbc.M115.677724.

  91. Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Lerner, A. G. et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 16, 250–264 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Menu, P. et al. ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis. 3, e261 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Kim, S. et al. Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways. Innate Immun. 20, 799–815 (2014).

    Article  PubMed  CAS  Google Scholar 

  95. Kim, M. S., Choi, M. S. & Han, S. N. High fat diet-induced obesity leads to proinflammatory response associated with higher expression of NOD2 protein. Nutr. Res. Pract. 5, 219–223 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Denou, E. et al. Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO Mol. Med. 7, 259–274 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. 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 

  98. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Youm, Y. H. et al. Elimination of the NLRP3-ASC inflammasome protects against chronic obesity-induced pancreatic damage. Endocrinology 152, 4039–4045 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Westwell-Roper, C., Nackiewicz, D., Dan, M. & Ehses, J. A. Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunol. Cell Biol. 92, 314–323 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Jourdan, T. et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates β cell loss in type 2 diabetes. Nat. Med. 19, 1132–1140 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Zambetti, L. P. & Mortellaro, A. NLRPs, microbiota, and gut homeostasis: unravelling the connection. J. Pathol. 233, 321–330 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. O'Connor, J. C. et al. IL-1β-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes. J. Immunol. 174, 4991–4997 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Mitroulis, I., Skendros, P. & Ritis, K. Targeting IL-1β in disease; the expanding role of NLRP3 inflammasome. Eur. J. Int. Med. 21, 157–163 (2010).

    Article  CAS  Google Scholar 

  108. McGettrick, A. F. & O'Neill, L. A. NLRP3 and IL-1β in macrophages as critical regulators of metabolic diseases. Diabetes Obesity Metab. 15, S19–S25 (2013).

    Article  CAS  Google Scholar 

  109. Freigang, S. et al. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis. Nat. Immunol. 14, 1045–1053 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Hara, N., Alkanani, A. K., Dinarello, C. A. & Zipris, D. Modulation of virus-induced innate immunity and type 1 diabetes by IL-1 blockade. Innate Immun. 20, 574–584 (2013).

    Article  PubMed  CAS  Google Scholar 

  111. Finucane, O. M. et al. Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1β secretion and insulin resistance despite obesity. Diabetes 64, 2116–2128 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Chen, K. et al. ATP-P2X4 signaling mediates NLRP3 inflammasome activation: a novel pathway of diabetic nephropathy. Int. J. Biochem. Cell Biol. 45, 932–943 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Nackiewicz, D. et al. TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair β cell insulin gene expression via IL-1 and IL-6. Diabetologia 57, 1645–1654 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Dalmas, E. et al. T cell-derived IL-22 amplifies IL-1β-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes 63, 1966–1977 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Gottlieb, P. A. et al. α1-antitrypsin therapy downregulates toll-like receptor-induced IL-1β responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes. J. Clin. Endocrinol. Metab. 99, E1418–E1426 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Wang, F. et al. Losartan inhibits LPS + ATP-induced IL-1β secretion from mouse primary macrophages by suppressing NALP3 inflammasome. Pharmazie 69, 680–684 (2014).

    CAS  PubMed  Google Scholar 

  117. Martinez-Micaelo, N., González-Abuín, N., Pinent, M., Ardévol, A. & Blay, M. Procyanidin B2 inhibits inflammasome-mediated IL-1β production in lipopolysaccharide-stimulated macrophages. Mol. Nutr. Food Res. 59, 262–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Miao, H. et al. Macrophage CGI-58 deficiency promotes IL-1β transcription by activating the SOCS3–FOXO1 pathway. Clin. Sci. 128, 493–506 (2015).

    Article  CAS  Google Scholar 

  119. Salminen, A., Kaarniranta, K. & Kauppinen, A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging 4, 166–175 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Lim, Y. M. et al. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat. Comm. 5, 4934 (2014).

    Article  CAS  Google Scholar 

  121. Liu, K. et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy 11, 271–284 (2015).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  122. Fasshauer, M. & Bluher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 36, 461–470 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Crujeiras, A. B. et al. Leptin resistance in obesity: an epigenetic landscape. Life Sci. http://dx.doi.org/10.1016/j.lfs.2015.05.003.

  124. Jitprasertwong, P., Jaedicke, K. M., Nile, C. J., Preshaw, P. M. & Taylor, J. J. Leptin enhances the secretion of interleukin (IL)-18, but not IL-1β, from human monocytes via activation of caspase-1. Cytokine 65, 222–230 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Owen, B. M., Mangelsdorf, D. J. & Kliewer, S. A. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 26, 22–29 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Asrih, M., Altirriba, J., Rohner-Jeanrenaud, F. & Jornayvaz, F. R. Ketogenic diet impairs FGF21 signaling and promotes differential inflammatory responses in the liver and white adipose tissue. PLoS ONE 10, e0126364 (2015).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  127. Liu, M. H. FGF-21 alleviates diabetes-associated vascular complications: inhibiting NF-κB/NLRP3 inflammasome-mediated inflammation? Int. J. Cardiol. 185, 320–321 (2015).

    Article  PubMed  Google Scholar 

  128. Roberts, R. L. et al. Interaction of the inflammasome genes CARD8 and NLRP3 in abdominal aortic aneurysms. Atherosclerosis 218, 123–126 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Li, Y., Xu, S., Jiang, B., Cohen, R. A. & Zang, M. Activation of sterol regulatory element binding protein and NLRP3 inflammasome in atherosclerotic lesion development in diabetic pigs. PLoS ONE 8, e67532 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Zheng, F., Xing, S., Gong, Z. & Xing, Q. NLRP3 inflammasomes show high expression in aorta of patients with atherosclerosis. Heart Lung Circ. 22, 746–750 (2013).

    Article  PubMed  Google Scholar 

  131. Anders, H. J. & Lech, M. NOD-like and Toll-like receptors or inflammasomes contribute to kidney disease in a canonical and a non-canonical manner. Kidney Int. 84, 225–228 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Mudaliar, H., Pollock, C. & Panchapakesan, U. Role of Toll-like receptors in diabetic nephropathy. Clin. Sci. 126, 685–694 (2014).

    Article  CAS  Google Scholar 

  133. Pillon, N. J. et al. Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promotes monocyte adhesion and impairs insulin transcytosis. Am. J. Physiol. Endocrinol. Metab. 309, E35–E44 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Rajamani, U. & Jialal, I. Hyperglycemia induces Toll-like receptor-2 and -4 expression and activity in human microvascular retinal endothelial cells: implications for diabetic retinopathy. J. Diabetes Res. 2014, 790902 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  135. Tang, S. C., Leung, J. C. & Lai, K. N. Diabetic tubulopathy: an emerging entity. Contrib. Nephrol. 170, 124–134 (2011).

    Article  PubMed  Google Scholar 

  136. Mudaliar, H. et al. The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells exposed to high glucose. PLoS ONE 9, e108844 (2014).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  137. Enlimomab Acute Stroke Trial Investigators. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57, 1428–1434 (2001).

  138. Salmela, K. et al. A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation 67, 729–736 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Musi, N. Phase 2 study of the role of pharmacologic inhibition of TLR4 with E5564 on glucose metabolism in insulin resistant subjects. ClinicalTrials.gov [online].

  140. Devaraj, S. et al. Knockout of toll-like receptor-2 attenuates both the proinflammatory state of diabetes and incipient diabetic nephropathy. Arterioscler. Thromb. Vasc. Biol. 31, 1796–1804 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  141. Sawa, Y., Takata, S., Hatakeyama, Y., Ishikawa, H. & Tsuruga, E. Expression of toll-like receptor 2 in glomerular endothelial cells and promotion of diabetic nephropathy by Porphyromonas gingivalis lipopolysaccharide. PLoS ONE 9, e97165 (2014).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  142. Mudaliar, H. et al. The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am. J. Physiol. Renal Physiol. 305, F143–F154 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Kaur, H., Chien, A. & Jialal, I. Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am. J. Physiol. Renal Physiol. 303, F1145–F1150 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Yang, M. et al. Proinflammatory CD14+CD16+ monocytes are associated with microinflammation in patients with type 2 diabetes mellitus and diabetic nephropathy uremia. Inflammation 35, 388–396 (2012).

    Article  CAS  PubMed  Google Scholar 

  145. Cha, J. J. et al. Renal protective effects of toll-like receptor 4 signaling blockade in type 2 diabetic mice. Endocrinology 154, 2144–2155 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Lin, M. et al. The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney Int. 83, 887–900 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Jialal, I., Major, A. M. & Devaraj, S. Global Toll-like receptor 4 knockout results in decreased renal inflammation, fibrosis and podocytopathy. J. Diabetes Complications 28, 755–761 (2014).

    Article  PubMed  Google Scholar 

  148. Saurus, P. et al. Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway. Cell Death Dis. 6, e1752 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Ma, J. et al. TLR4 activation promotes podocyte injury and interstitial fibrosis in diabetic nephropathy. PLoS ONE 9, e97985 (2014).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  150. Verzola, D. et al. Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int. 86, 1229–1243 (2014).

    Article  CAS  PubMed  Google Scholar 

  151. Oh, D. J., Kim, H. R., Lee, M. K. & Woo, Y. S. Profile of human β-defensins 1,2 and proinflammatory cytokines (TNF-α, IL-6) in patients with chronic kidney disease. Kidney Blood Press. Res. 37, 602–610 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Navarro-González, J. F., Jarque, A., Muros, M., Mora, C. & García, J. Tumor necrosis factor-α as a therapeutic target for diabetic nephropathy. Cytokine Growth Factor Rev. 20, 165–173 (2009).

    Article  PubMed  CAS  Google Scholar 

  153. Navarro, J. F. & Mora-Fernández, C. The role of TNF-α in diabetic nephropathy: pathogenic and therapeutic implications. Cytokine Growth Factor Rev. 17, 441–450 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Du, P. et al. NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int. 84, 265–276 (2013).

    Article  CAS  PubMed  Google Scholar 

  155. Shang, J. et al. Identification of NOD2 as a novel target of RNA-binding protein HuR: evidence from NADPH oxidase-mediated HuR signaling in diabetic nephropathy. Free Radic. Biol. Med. 79, 217–227 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. Wang, C., Pan, Y., Zhang, Q. Y., Wang, F. M. & Kong, L. D. Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. PLoS ONE 7, e38285 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Kim, S. M. et al. Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy. Am. J. Physiol. Renal Physiol. 308, F993–F1003 (2015).

    Article  CAS  PubMed  Google Scholar 

  158. Shahzad, K. et al. Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 87, 74–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  159. Gao, P. et al. NADPH oxidase-induced NALP3 inflammasome activation is driven by thioredoxin-interacting protein which contributes to podocyte injury in hyperglycemia. J. Diabetes Res. 2015, 504761 (2015).

    PubMed Central  PubMed  Google Scholar 

  160. Li, J. et al. TLR4 is required for the obesity-induced pancreatic β cell dysfunction. Acta Biochim. Biophys. Sin. 45, 1030–1038 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Zhou, Y. J., Zhou, H., Li, Y. & Song, Y. L. NOD1 activation induces innate immune responses and insulin resistance in human adipocytes. Diabetes Metab. 38, 538–543 (2012).

    Article  CAS  PubMed  Google Scholar 

  162. Brenner, C. et al. TLR signalling and adapter utilization in primary human in vitro differentiated adipocytes. Scand. J. Immunol. 76, 359–370 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Kopp, A. et al. Toll-like receptor ligands cause proinflammatory and prodiabetic activation of adipocytes via phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase but not interferon regulatory factor-3. Endocrinology 151, 1097–1108 (2010).

    Article  CAS  PubMed  Google Scholar 

  164. Liu, P., Li, F., Qiu, M. & He, L. Expression and cellular distribution of TLR4, MyD88, and NF-κB in diabetic renal tubulointerstitial fibrosis, in vitro and in vivo. Diabetes Res. Clin. Pract. 105, 206–216 (2014).

    Article  CAS  PubMed  Google Scholar 

  165. Jin, H. et al. Synergistic effects of leflunomide and benazepril in streptozotocin-induced diabetic nephropathy. Nephron Exp. Nephrol. 126, 148–156 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Kurihara, T. & Bravo, R. Cloning and functional expression of mCCR2, a murine receptor for the C-C chemokines JE and FIC. J. Biol. Chem. 271, 11603–11607 (1996).

    Article  CAS  PubMed  Google Scholar 

  167. Panee, J. Monocyte chemoattractant protein 1 (MCP-1) in obesity and diabetes. Cytokine 60, 1–12 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  168. Roca, H. et al. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J. Biol. Chem. 284, 34342–34354 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  169. Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  170. Gnudi, L. A new chance to beat diabetic kidney disease: innate immunity and MCP-1: a matter of good and bad macrophages? Nephrol. Dial. Transplant. 30, 525–527 (2015).

    Article  CAS  PubMed  Google Scholar 

  171. de Zeeuw, D. et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 3, 687–696 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Li, J. et al. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res. 75, 508–518 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Gao, P. et al. Thioredoxin-interacting protein mediates NALP3 inflammasome activation in podocytes during diabetic nephropathy. Biochim. Biophys. Acta 1843, 2448–2460 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Solini, A. et al. The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation. J. Pathol. 231, 342–353 (2013).

    Article  CAS  PubMed  Google Scholar 

  175. Boini, K. M. et al. Activation of inflammasomes in podocyte injury of mice on the high fat diet: effects of ASC gene deletion and silencing. Biochim. Biophys. Acta 1843, 836–845 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  176. Takata, S., Sawa, Y., Uchiyama, T. & Ishikawa, H. Expression of Toll-like receptor 4 in glomerular endothelial cells under diabetic conditions. Acta Histochem. Cytochem. 46, 35–42 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

J.W. and H.M. are supported in part by grants from the Japanese Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant numbers 25126716 and 26293218). The authors would like to thank Dr Atsuko Nakatsuka (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan) for valuable discussion and critical editing of the manuscript.

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  1. Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700–8558, Kita-ku, Japan

    Jun Wada & Hirofumi Makino

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J.W. researched the data and wrote the article. J.W. and H.M. provided a substantial contribution to discussions of the content and to review and/or editing of the manuscript before submission.

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Correspondence to Jun Wada.

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J.W. receives speaker honoraria from Astellas, Boehringer Ingelheim, Novartis, Novo Nordisk, and Tanabe Mitsubishi, and receives grant support from Bayer, Daiichi Sankyo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Otsuka, Torii, Pfizer, Takeda, Taisho Toyama, and Tanabe Mitsubishi. H.M. is a consultant for AbbVie, Astellas and Teijin, receives speaker honoraria from Astellas, Boehringer-Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Takeda, and Tanabe Mitsubishi, and receives grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Takeda, and Tanabe Mitsubishi.

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Wada, J., Makino, H. Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol 12, 13–26 (2016). https://doi.org/10.1038/nrneph.2015.175

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