Angeborene Immunität und Adipositas – Die Rolle der Nod-like-Rezeptoren (NLR)

Zusammenfassung

Allgemein wird angenommen, dass die mit Adipositas assoziierten Komorbiditäten, vor allem das metabolische Syndrom, wesentlich durch niederschwellige Entzündungsreaktionen, vorrangig im Fettgewebe, ausgelöst werden. In Mausmodellen spielt hierbei die Freisetzung proinflammatorischer Zytokine wie Interleukin-1 beta (IL-1β) und die Prägung von Immunzellen zu einem proinflammatorischen Phänotyp im Fettgewebe eine wichtige Rolle. Die zugrundeliegenden genetischen und molekularen Determinanten sind jedoch noch nicht im Detail verstanden.

Eine Reihe neuer Arbeiten zeigt, dass Proteine der Nod-like-Rezeptoren(NLR)-Familie wichtige Rollen bei der Entstehung und Ausprägung von Adipositas und Adipositas-assoziierten Entzündungsreaktionen spielen. In diesem Artikel betrachten wir den aktuellen Stand der Forschung auf diesem Gebiet und diskutieren offene Fragen zur Relevanz dieser Daten für das Verständnis der Entstehung von Adipositas und des metabolischen Syndroms im Menschen.

Abstract

It is generally assumed that the comorbidities associated with obesity, in particular the metabolic syndrome, are triggered by low-grade inflammatory reactions, especially in adipose tissue. In mouse models, the release of proinflammatory cytokines such as interleukin-1 beta (IL-1β) and the imprinting of immune cells into a pro-inflammatory phenotype in adipose tissue play important roles. However, the underlying genetic and molecular determinants are hitherto not well understood.

A number of recent studies revealed that proteins of the Nod-like-receptor (NLR) family play important roles in the development and control of obesity and obesity-associated inflammatory reactions. Here we review the current state of research in this area and discuss open questions about the relevance of this data for understanding the development of obesity and metabolic syndrome in humans.

Schlüsselwörter

NLRP3 - IL-1β - Nod1 - Nod2 - NLRP12 - HFD - Mikrobiota

Keywords

NLRP3 - IL-1β - Nod1 - Nod2 - NLRP12 - HFD - microbiota

• Literatur

• 1 Ng M, Fleming T, Robinson M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766-781
• 2 Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 1415-1428
• 3 Konnopka A, Dobroschke A, Lehnert T. et al. [The Costs of Overweight and Obesity: a Systematic Review]. Gesundheitswesen 2018; 80: 471-481
• 4 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867
• 5 Schertzer JD, Klip A. Give a NOD to insulin resistance. American journal of physiology Endocrinology and metabolism 2011; 301: E585-586
• 6 Marchesini G, Bugianesi E, Forlani G. et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology (Baltimore, Md) 2003; 37: 917-923
• 7 Mehta R, Neupane A, Wang L. et al. Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects. BMC Gastroenterol 2014; 14: 208
• 8 Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219-246
• 9 Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord 2003; 27 (Suppl. 03) S49-52
• 10 Weisberg SP, McCann D, Desai M. et al. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation 2003; 112: 1796-1808
• 11 Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annual review of immunology 2011; 29: 415-445
• 12 Haneklaus M, O’Neill LA. NLRP3 at the interface of metabolism and inflammation. Immunol Rev 2015; 265: 53-62
• 13 Legrand-Poels S, Esser N, L’Homme L. et al. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem Pharmacol 2014; 92: 131-141
• 14 Kim YK, Shin JS, Nahm MH. NOD-Like Receptors in Infection, Immunity, and Diseases. Yonsei Med J 2016; 57: 5-14
• 15 Motta V, Soares F, Sun T. et al. NOD-like receptors: versatile cytosolic sentinels. Physiol Rev 2015; 95: 149-178
• 16 Arnold C, Kienes I, Sowa AS, Kufer TA. NOD-like Receptors. Chichester: eLS John Wiley & Sons, Ltd; 2018. DOI: 10.1002/9780470015902.a0026236
• 17 Duewell P, Kono H, Rayner KJ. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464: 1357-1361
• 18 Ting JP, Lovering RC, Alnemri ES. et al. The NLR gene family: a standard nomenclature. Immunity 2008; 28: 285-287
• 19 Jo EK, Kim JK, Shin DM. et al. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol 2016; 13: 148-159
• 20 Munoz-Planillo R, Kuffa P, Martinez-Colon G. et al. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 2013; 38: 1142-1153
• 21 Petrilli V, Papin S, Dostert C. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 2007; 14: 1583-1589
• 22 Vladimer GI, Marty-Roix R, Ghosh S. et al. Inflammasomes and host defenses against bacterial infections. Curr Opin Microbiol 2013; 16: 23-31
• 23 Meissner TB, Li A, Biswas A. et al. NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci U S A 2010; 107: 13794-13799
• 24 Steimle V, Otten LA, Zufferey M. et al. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). (Erstdruck Cell 1993; 75:135 – 146.) J Immunol 2007; 178: 6677-6688
• 25 Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nature reviews Immunology 2018; DOI: 10.1038/nri.2017.136.
• 26 Philpott DJ, Sorbara MT, Robertson SJ. et al. NOD proteins: regulators of inflammation in health and disease. Nature reviews Immunology 2014; 14: 9-23
• 27 Schertzer JD, Tamrakar AK, Magalhaes JG. et al. NOD1 activators link innate immunity to insulin resistance. Diabetes 2011; 60: 2206-2215
• 28 Chan KL, Tam TH, Boroumand P. et al. Circulating NOD1 Activators and Hematopoietic NOD1 Contribute to Metabolic Inflammation and Insulin Resistance. Cell Rep 2017; 18: 2415-2426
• 29 Purohit JS, Hu P, Burke SJ. et al. The effects of NOD activation on adipocyte differentiation. Obesity 2013; 21: 737-747
• 30 Chi W, Dao D, Lau TC. et al. Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1. PloS one 2014; 9: e97675
• 31 Zhao L, Hu P, Zhou Y. et al. NOD1 activation induces proinflammatory gene expression and insulin resistance in 3T3-L1 adipocytes. American journal of physiology Endocrinology and metabolism 2011; 301: E587-598
• 32 Duggan BM, Foley KP, Henriksbo BD. et al. Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia. Scientific reports 2017; 7: 1578
• 33 Zhou YJ, Zhou H, Li Y. et al. NOD1 activation induces innate immune responses and insulin resistance in human adipocytes. Diabetes & metabolism 2012; 38: 538-543
• 34 Shiny A, Regin B, Balachandar V. et al. Convergence of innate immunity and insulin resistance as evidenced by increased nucleotide oligomerization domain (NOD) expression and signaling in monocytes from patients with type 2 diabetes. Cytokine 2013; 64: 564-570
• 35 Lappas M. NOD1 expression is increased in the adipose tissue of women with gestational diabetes. The Journal of endocrinology 2014; 222: 99-112
• 36 Zhou YJ, Liu C, Li CL. et al. Increased NOD1, but not NOD2, activity in subcutaneous adipose tissue from patients with metabolic syndrome. Obesity 2015; DOI: 10.1002/oby.21113.
• 37 Denou E, Lolmede K, Garidou L. et al. Defective NOD2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO molecular medicine 2015; 7: 259-274
• 38 Cavallari JF, Fullerton MD, Duggan BM. et al. Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4. Cell Metab 2017; 25: 1063-1074, e1063
• 39 Rodriguez-Nunez I, Caluag T, Kirby K. et al. Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction. Scientific reports 2017; 7: 548
• 40 Robertson SJ, Zhou JY, Geddes K. et al. Nod1 and Nod2 signaling does not alter the composition of intestinal bacterial communities at homeostasis. Gut microbes 2013; 4: 222-231
• 41 Serino M, Luche E, Gres S. et al. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 2012; 61: 543-553
• 42 Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242-249
• 43 Backhed F, Manchester JK, Semenkovich CF. et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the United States of America 2007; 104: 979-984
• 44 Cani PD, Amar J, Iglesias MA. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56: 1761-1772
• 45 Cani PD, Bibiloni R, Knauf C. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57: 1470-1481
• 46 Luck H, Tsai S, Chung J. et al. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab 2015; 21: 527-542
• 47 Erridge C, Attina T, Spickett CM. et al. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 2007; 86: 1286-1292
• 48 Zhao L, Kwon MJ, Huang S. et al. Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells. The Journal of biological chemistry 2007; 282: 11618-11628
• 49 Zhou YJ, Tang YS, Song YL. et al. Saturated fatty acid induces insulin resistance partially through nucleotide-binding oligomerization domain 1 signaling pathway in adipocytes. Chin Med Sci J 2013; 28: 211-217
• 50 Dasu MR, Jialal I. Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. American journal of physiology Endocrinology and metabolism 2011; 300: E145-154
• 51 Lancaster GI, Langley KG, Berglund NA. et al. Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism. Cell Metab 2018; 27: 1096-1110, e1095
• 52 Talukdar S, Olefsky JM, Osborn O. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol Sci 2011; 32: 543-550
• 53 Ozbayer C, Kurt H, Kebapci MN. et al. Effects of genetic variations in the genes encoding NOD1 and NOD2 on type 2 diabetes mellitus and insulin resistance. J Clin Pharm Ther 2017; 42: 98-102
• 54 Cuda C, Badawi A, Karmali M. et al. Effects of polymorphisms in nucleotide-binding oligomerization domains 1 and 2 on biomarkers of the metabolic syndrome and type II diabetes. Genes Nutr 2012; 7: 427-435
• 55 Haile PA, Votta BJ, Marquis RW. et al. The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase. Journal of medicinal chemistry 2016; 59: 4867-4880
• 56 Nachbur U, Stafford CA, Bankovacki A. et al. A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. Nature communications 2015; 6: 6442
• 57 Neerincx A, Rodriguez GM, Steimle V. et al. NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. Journal of immunology 2012; 188: 4940-4950
• 58 Staehli F, Ludigs K, Heinz LX. et al. NLRC5 deficiency selectively impairs MHC class I – dependent lymphocyte killing by cytotoxic T cells. Journal of immunology 2012; 188: 3820-3828
• 59 Meeks KAC, Henneman P, Venema A. et al. An epigenome-wide association study in whole blood of measures of adiposity among Ghanaians: the RODAM study. Clin Epigenetics 2017; 9: 103
• 60 Benko S, Kovacs EG, Hezel F. et al. NLRC5 Functions beyond MHC I Regulation – What Do We Know So Far?. Front Immunol 2017; 8: 150
• 61 Carneiro LA, Fritz JO, Kufer TA. et al. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins. EcoSal Plus 2009; 3 DOI: 10.1128/ecosalplus.8.8.3.
• 62 Sepehri Z, Kiani Z, Afshari M. et al. Inflammasomes and type 2 diabetes: An updated systematic review. Immunol Lett 2017; 192: 97-103
• 63 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821-832
• 64 Serena C, Keiran N, Ceperuelo-Mallafre V. et al. Obesity and Type 2 Diabetes Alters the Immune Properties of Human Adipose Derived Stem Cells. Stem Cells 2016; 34: 2559-2573
• 65 Esser N, L’Homme L, De Roover A. et al. Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue. Diabetologia 2013; 56: 2487-2497
• 66 Yin Z, Deng T, Peterson LE. et al. Transcriptome analysis of human adipocytes implicates the NOD-like receptor pathway in obesity-induced adipose inflammation. Mol Cell Endocrinol 2014; 394: 80-87
• 67 Bando S, Fukuda D, Soeki T. et al. Expression of NLRP3 in subcutaneous adipose tissue is associated with coronary atherosclerosis. Atherosclerosis 2015; 242: 407-414
• 68 Vandanmagsar B, Youm YH, Ravussin A. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011; 17: 179-188
• 69 Nagareddy PR, Kraakman M, Masters SL. et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 2014; 19: 821-835
• 70 Stienstra R, van Diepen JA, Tack CJ. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A 2011; 108: 15324-15329
• 71 Youm YH, Adijiang A, Vandanmagsar B. et al. Elimination of the NLRP3-ASC inflammasome protects against chronic obesity-induced pancreatic damage. Endocrinology 2011; 152: 4039-4045
• 72 Wen H, Gris D, Lei Y. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 2011; 12: 408-415
• 73 Capurso C, Capurso A. From excess adiposity to insulin resistance: the role of free fatty acids. Vascul Pharmacol 2012; 57: 91-97
• 74 Jager J, Gremeaux T, Cormont M. et al. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 2007; 148: 241-251
• 75 Engin AB. Adipocyte-Macrophage Cross-Talk in Obesity. Adv Exp Med Biol 2017; 960: 327-343
• 76 Stienstra R, Joosten LA, Koenen T. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 2010; 12: 593-605
• 77 Masters SL, Dunne A, Subramanian SL. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 2010; 11: 897-904
• 78 Westwell-Roper CY, Chehroudi CA, Denroche HC. et al. IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice. Diabetologia 2015; 58: 575-585
• 79 Rheinheimer J, de Souza BM, Cardoso NS. et al. Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review. Metabolism 2017; 74: 1-9
• 80 L’Homme L, Esser N, Riva L. et al. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res 2013; 54: 2998-3008
• 81 Macia L, Tan J, Vieira AT. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nature communications 2015; 6: 6734
• 82 Vieira AT, Macia L, Galvao I. et al. A Role for Gut Microbiota and the Metabolite-Sensing Receptor GPR43 in a Murine Model of Gout. Arthritis Rheumatol 2015; 67: 1646-1656
• 83 Zhou R, Tardivel A, Thorens B. et al. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 2010; 11: 136-140
• 84 Traba J, Sack MN. The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome. Cell Mol Life Sci 2017; 74: 1777-1791
• 85 Furukawa S, Fujita T, Shimabukuro M. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761
• 86 Heid ME, Keyel PA, Kamga C. et al. Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. Journal of immunology (Baltimore, Md: 1950) 2013; 191: 5230-5238
• 87 Zhou R, Yazdi AS, Menu P. et al. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011; 469: 221-225
• 88 Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 2012; 18: 59-68
• 89 Menu P, Mayor A, Zhou R. et al. ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis 2012; 3: e261
• 90 Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009; 6: 399-409
• 91 Zheng F, Xing S, Gong Z. et al. NLRP3 inflammasomes show high expression in aorta of patients with atherosclerosis. Heart Lung Circ 2013; 22: 746-750
• 92 Paramel Varghese G, Folkersen L, Strawbridge RJ. et al. NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. J Am Heart Assoc 2016; 5 DOI: 10.1161/JAHA.115.003031.
• 93 Hendrikx T, Jeurissen ML, van Gorp PJ. et al. Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr(-/-) mice. FEBS J 2015; 282: 2327-2338
• 94 Gage J, Hasu M, Thabet M. et al. Caspase-1 deficiency decreases atherosclerosis in apolipoprotein E-null mice. Can J Cardiol 2012; 28: 222-229
• 95 Mallat Z, Corbaz A, Scoazec A. et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 2001; 89: E41-45
• 96 Kirii H, Niwa T, Yamada Y. et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2003; 23: 656-660
• 97 Christ A, Gunther P, Lauterbach MAR. et al. Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming. Cell 2018; 172: 162-175, e114
• 98 Rajamäki K, Lappalainen J, Öörni K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 2010; 5 e11765. DOI: 10.1371/journal.pone.0011765.
• 99 Peng K, Liu L, Wei D. et al. P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation. Int J Mol Med 2015; 35: 1179-1188
• 100 Stachon P, Heidenreich A, Merz J. et al. P2X7 Deficiency Blocks Lesional Inflammasome Activity and Ameliorates Atherosclerosis in Mice. Circulation 2017; 135: 2524-2533
• 101 Guo C, Chi Z, Jiang D. et al. Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages. Immunity 2018; 49: 842-856 e847
• 102 Garcia MC, Wernstedt I, Berndtsson A. et al. Mature-onset obesity in interleukin-1 receptor I knockout mice. Diabetes 2006; 55: 1205-1213
• 103 Chida D, Osaka T, Hashimoto O. et al. Combined interleukin-6 and interleukin-1 deficiency causes obesity in young mice. Diabetes 2006; 55: 971-977
• 104 Henao-Mejia J, Elinav E, Jin C. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482: 179-185
• 105 del Rey A, Besedovsky H. Interleukin 1 affects glucose homeostasis. The American journal of physiology 1987; 253: R794-798
• 106 Larsen CM, Faulenbach M, Vaag A. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007; 356: 1517-1526
• 107 Dror E, Dalmas E, Meier DT. et al. Postprandial macrophage-derived IL-1beta stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nature immunology 2017; 18: 283-292
• 108 Rothe H, Hausmann A, Casteels K. et al. IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis. J Immunol 1999; 163: 1230-1236
• 109 Elinav E, Strowig T, Kau AL. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011; 145: 745-757
• 110 Chen GY, Liu M, Wang F. et al. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. Journal of immunology (Baltimore, Md: 1950) 2011; 186: 7187-7194
• 111 Wree A, McGeough MD, Pena CA. et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl) 2014; 92: 1069-1082
• 112 Elhage R, Jawien J, Rudling M. et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc Res 2003; 59: 234-240
• 113 Esser N, Paquot N, Scheen AJ. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs 2015; 24: 283-307
• 114 Zaki MH, Vogel P, Malireddi RK. et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer cell 2011; 20: 649-660
• 115 Allen IC, Wilson JE, Schneider M. et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity 2012; 36: 742-754
• 116 Truax AD, Chen L, Tam JW. et al. The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell host & microbe 2018; 24: 364-378.e366
• 117 Hensen J, Howard CP, Walter V. et al. Impact of interleukin-1beta antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab 2013; 39: 524-531
• 118 Ridker PM, Howard CP, Walter V. et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012; 126: 2739-2748
• 119 Cavelti-Weder C, Babians-Brunner A, Keller C. et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care 2012; 35: 1654-1662
• 120 Sloan-Lancaster J, Abu-Raddad E, Polzer J. et al. Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1beta antibody, in patients with type 2 diabetes. Diabetes Care 2013; 36: 2239-2246
• 121 van Asseldonk EJ, Stienstra R, Koenen TB. et al. Treatment with Anakinra improves disposition index but not insulin sensitivity in nondiabetic subjects with the metabolic syndrome: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2011; 96: 2119-2126
• 122 Ridker PM, Everett BM, Thuren T. et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017; 377: 1119-1131