Tissue factor pathways linking obesity and inflammation

Summary

Obesity is a major cause for a spectrum of metabolic syndrome-related diseases that include insulin resistance, type 2 diabetes, and steatosis of the liver. Inflammation elicited by macrophages and other immune cells contributes to the metabolic abnormalities in obesity. In addition, coagulation activation following tissue factor (TF) upregulation in adipose tissue is frequently found in obese patients and particularly associated with diabetic complications. Genetic and pharmacological evidence indicates that TF makes significant contributions to the development of the metabolic syndrome by signaling through G protein-coupled protease activated receptors (PARs). Adipocyte TF-PAR2 signaling contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas hematopoietic TF-PAR2 signaling is a major cause for adipose tissue inflammation, hepatic steatosis and inflammation, as well as insulin resistance. In the liver of mice on a high fat diet, PAR2 signaling increases transcripts of key regulators of gluconeogenesis, lipogenesis and inflammatory cytokines. Increased markers of hepatic gluconeogenesis correlate with decreased activation of AMP-activated protein kinase (AMPK), a known regulator of these pathways and a target for PAR2 signaling. Clinical markers of a TF-induced prothrombotic state may thus indicate a risk in obese patient for developing complications of the metabolic syndrome.

Zusammenfassung

Adipositas führt zu extrinsischer Gerinnungsaktivierung durch den zellständigen Rezeptor Tissue Factor (TF) im Fettgewebe. Studien in Mausmodellen belegen, dass TF und der durch die von TF-assozierten Proteasen stimulierten Protease Activated Receptors 2 (PAR2) in der Entwicklung der Adipositas und deren pathologischen Konsequenzen eine wesentliche Rolle spielen. Inhibierung von TF und der TF-PAR2-Signaltransduktionswege verbessern nicht nur die Thromboseneigung, sondern auch das Entzündungsgeschehen im Fettgewebe und die Entwicklung von Diabetes und Leberdysfunktion.

Keywords

TF - PARs

Schlüsselwörter

TF - PARs

• References

• 1 Samad F, Ruf W. Inflammation, obesity and thrombosis. Blood 2013; 122: 3415-3422.
• 2 Ayer JG, Song C, Steinbeck K. et al. Increased tissue factor activity in monocytes from obese young adults. Clin Exp Pharmacol Physiol 2010; 37: 1049-1054.
• 3 Badeanlou L, Furlan-Freguia C, Yang G. et al. Tissue factor-PAR2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med 2011; 17: 1490-1497.
• 4 Samad F, Pandey M, Loskutoff DJ. Tissue factor gene expression in the adipose tissues of obese mice. Proc Natl Acad Sci USA 1998; 95: 7591-7596.
• 5 Lijnen HR, Van HM, Hemmeryckx B. Caloric restriction improves coagulation and inflammation profile in obese mice. Thromb Res 2012; 129: 74-79.
• 6 Shetty PB, Tang H, Tayo BO. et al. Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping. J Hypertens 2012; 30: 1970-1976.
• 7 Ruf W, Dickinson CD. Allosteric regulation of the cofactor-dependent serine protease coagulation factor VIIa. Trends Cardiovasc Med 1998; 08: 350-356.
• 8 Ahamed J, Niessen F, Kurokawa T. et al. Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia. Blood 2007; 109: 5251-5259.
• 9 Dorfleutner A, Hintermann E, Tarui T. et al. Crosstalk of integrin a3b1 and tissue factor in cell migration. Mol Biol Cell 2004; 15: 4416-4425.
• 10 Ott I, Fischer EG, Miyagi Y. et al. A role for tissue factor in cell adhesion and migration mediated by interaction with actin binding protein 280. J Cell Biol 1998; 140: 1241-1253.
• 11 Ott I, Weigand B, Michl R. et al. Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38. Circulation 2005; 111: 349-355.
• 12 Ettelaie C, Elkeeb AM, Maraveyas A, Collier ME. p38alpha phosphorylates serine 258 within the cytoplasmic domain of tissue factor and prevents its incorporation into cell-derived microparticles. Biochim Biophys Acta 2013; 1833: 613-621.
• 13 Srinivasan R, Ozhegov E, van den Berg YW. et al. Splice variants of tissue factor promote monocyteendothelial interactions by triggering the expression of cell adhesion molecules via integrinmediated signaling. J Thromb Haemost 2011; 09: 2087-2096.
• 14 Van den Berg YW, van den Hengel LG, Myers HR. et al. Alternatively spliced tissue factor induces angiogenesis through integrin ligation. Proc Natl Acad Sci USA 2009; 106: 19497-19502.
• 15 Versteeg HH, Schaffner F, Kerver M. et al. Inhibition of tissue factor signaling suppresses tumor growth. Blood 2008; 111: 190-199.
• 16 Langer F, Spath B, Fischer C. et al. Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase. Blood 2013; 121: 2324-2335.
• 17 Furlan-Freguia C, Marchese P, Gruber A. et al. P2X7 receptor signaling contributes to tissue factor-dependent thrombosis in mice. J Clin Invest 2011; 121: 2932-2944.
• 18 Ruf W, Disse J, Carneiro-Lobo TC. et al. Tissue factor and cell signalling in cancer progression and thrombosis. J Thromb Haemost 2011; 09 (Suppl. 01) 306-315.
• 19 Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci USA 2001; 98: 7742-7747.
• 20 Disse J, Petersen HH, Larsen KS. et al. The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem 2011; 286: 5756-5767.
• 21 Rothmeier AS, Ruf W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol 2012; 34: 133-149.
• 22 Mansuy-Aubert V, Zhou QL, Xie X. et al. Imbalance between neutrophil elastase and its inhibitor a1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure. Cell Metab 2013; 17: 534-548.
• 23 Larsen KS, Ostergaard H, Olsen OH. et al. Engineering of substrate selectivity for tissue factor-factor VIIa complex signaling through protease activated receptor 2. J Biol Chem 2010; 285: 19959-19966.
• 24 Wang P, Jiang Y, Wang Y. et al. Beta-arrestin inhibits CAMKKbeta-dependent AMPK activation downstream of protease-activated-receptor-2. BMC Biochem. 2010; 11: 36.
• 25 Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219-246.
• 26 Patsouris D, Li PP, Thapar D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008; 08: 301-319.
• 27 Randolph GJ, Luther T, Albrecht S. et al. Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro. Blood 1998; 92: 4167-4177.
• 28 Feral CC, Neels JG, Kummer C. et al. Blockade of alpha4 integrin signaling ameliorates the metabolic consequences of high-fat diet-induced obesity. Diabetes 2008; 57: 1842-1851.
• 29 Redecha P, Franzke CW, Ruf W. et al. Activation of neutrophils by the Tissue Factor-Factor VIIaPAR2 axis mediates fetal death in antiphospholipid syndrome. J Clin Invest 2008; 118: 3453-3461.
• 30 Noorbakhsh F, Tsutsui S, Vergnolle N. et al. Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J Exp Med 2006; 203: 425-435.
• 31 Nhu QM, Shirey K, Teijaro JR. et al. Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo. Mucosal Immunol 2010; 03: 29-39.
• 32 Rallabhandi P, Nhu QM, Toshchakov VY. et al. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. J Biol Chem 2008; 283: 24314-24325.
• 33 Nhu QM, Shirey KA, Pennini M. et al. Proteinase-activated receptor 2 activation promotes an antiinflammatory and alternatively activated phenotype in LPS-stimulated murine macrophages. Innate Immun 2011; 18: 193-203.
• 34 Massberg S, Grahl L, von Bruehl ML. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16: 887-896.
• 35 Ahamed J, Belting M, Ruf W. Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1. Blood 2005; 105: 2384-2391.
• 36 Ramachandran R, Mihara K, Chung H. et al. Neutrophil elastase acts as a biased agonist for proteinase activated receptor-2 (PAR2). J Biol Chem 2011; 286: 24638-24648.
• 37 Li P, Lu M, Nguyen MT. et al. Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J Biol Chem 2010; 285: 15333-15345.
• 38 Oh DY, Talukdar S, Bae EJ. et al. GPR120 is an omega-3 fatty acid receptor mediating potent antiinflammatory and insulin-sensitizing effects. Cell 2010; 142: 687-698.
• 39 Wang J, Chakrabarty S, Bui Q. et al. Hematopoietic Tissue Factor-protease activated receptor 2 signaling promotes hepatic inflammation and contributes to pathways of gluconeogenesis and steatosis in obese mice. Am J Pathol 2015; 185: 524-535.
• 40 Mihara M, Aihara K, Ikeda Y. et al. Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice. Endocrinology 2010; 151: 513-519.
• 41 Kassel KM, Owens APIii, Rockwell CE. et al. Protease-Activated Receptor 1 and Hematopoietic Cell Tissue Factor Are Required for Hepatic Steatosis in Mice Fed a Western Diet. Am J Pathol 2011; 179: 2278-2289.
• 42 Luyendyk JP, Sullivan BP, Guo GL, Wang R. Tissue factor-deficiency and protease activated receptor-1-deficiency reduce inflammation elicited by diet-induced steatohepatitis in mice. Am J Pathol 2010; 176: 177-186.
• 43 Sullivan BP, Kopec AK, Joshi N. et al. Hepatocyte tissue factor activates the coagulation cascade in mice. Blood 2013; 121: 1868-1874.
• 44 Lim J, Iyer A, Liu L. et al. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J 2013; 27: 4757-4767.
• 45 Ageno W, Di Minno MN, Ay C. et al. Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis. Arterioscler Thromb Vasc Biol 2014; 34: 2478-2485.
• 46 Ay C, Tengler T, Vormittag R. et al. Venous thromboembolism – a manifestation of the metabolic syndrome. Haematologica 2007; 92: 374-380.
• 47 Ay L, Hoellerl F, Ay C. et al. Thrombin generation in type 2 diabetes with albuminuria and macrovascular disease. Eur J Clin Invest 2012; 42: 470-477.