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The role of ADAM17 in metabolic inflammation

      Abstract

      The TNF-alpha Converting Enzyme (TACE), also called ADAM17 (A Disintegrin and A Metalloproteinase 17) is a type I transmembrane metalloproteinase involved in the shedding of the extracellular domain of several transmembrane proteins such as cytokines, growth factors, receptors and adhesion molecules. Some of these proteolytic events are part of cleavage cascades known as Regulated Intramembrane Proteolysis and lead to intracellular signaling. Evidence is provided that ADAM17 plays a role in atherosclerosis, in adipose tissue metabolism, insulin resistance and diabetes. The multitude of substrates cleaved by ADAM17 makes this enzyme an attractive candidate to study its role in inflammatory disorders. This review is focused on effects of ADAM17 in major metabolic tissues.

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      References

        • Scheller J.
        • Chalaris A.
        • Garbers C.
        • et al.
        ADAM17: a molecular switch to control inflammation and tissue regeneration.
        Trends in Immunology. 2011; 32: 380-387
        • Peschon J.J.
        • Slack J.L.
        • Reddy P.
        • et al.
        An essential role for ectodomain shedding in mammalian development.
        Science (New York, N.Y). 1998; 282: 1281-1284
        • Solomon K.A.
        • Pesti N.
        • Wu G.
        • et al.
        Cutting edge: a dominant negative form of TNF-alpha converting enzyme inhibits proTNF and TNFRII secretion.
        Journal of Immunology. 1999; 163: 4105-4108
        • Lorenzen I.
        • Lokau J.
        • Dusterhoft S.
        • et al.
        The membrane-proximal domain of A Disintegrin and Metalloprotease 17 (ADAM17) is responsible for recognition of the interleukin-6 receptor and interleukin-1 receptor II.
        FEBS Letters. 2012; 586: 1093-1100
        • Nuttall R.K.
        • Sampieri C.L.
        • Pennington C.J.
        • et al.
        Expression analysis of the entire MMP and TIMP gene families during mouse tissue development.
        FEBS Letters. 2004; 563: 129-134
        • Xu P.
        • Liu J.
        • Sakaki-Yumoto M.
        • et al.
        TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association.
        Science Signaling. 2012; 5: ra34
        • McIlwain D.R.
        • Lang P.A.
        • Maretzky T.
        • et al.
        iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS.
        Science (New York, N.Y). 2012; 335: 229-232
        • Adrain C.
        • Zettl M.
        • Christova Y.
        • et al.
        Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.
        Science (New York, N.Y). 2012; 335: 225-228
        • Gill S.E.
        • Huizar I.
        • Bench E.M.
        • et al.
        Tissue inhibitor of metalloproteinases 3 regulates resolution of inflammation following acute lung injury.
        The American Journal of Pathology. 2010; 176: 64-73
        • Federici M.
        • Hribal M.L.
        • Menghini R.
        • et al.
        Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha.
        The Journal of Clinical Investigation. 2005; 115: 3494-3505
        • Chavey C.
        • Mari B.
        • Monthouel M.N.
        • et al.
        Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation.
        The Journal of Biological Chemistry. 2003; 278: 11888-11896
        • Cardellini M.
        • Menghini R.
        • Luzi A.
        • et al.
        Decreased IRS2 and TIMP3 expression in monocytes from offspring of type 2 diabetic patients is correlated with insulin resistance and increased intima-media thickness.
        Diabetes. 2011; 60: 3265-3270
        • Andersson C.X.
        • Gustafson B.
        • Hammarstedt A.
        • et al.
        Inflamed adipose tissue, insulin resistance and vascular injury.
        Diabetes/metabolism Research and Reviews. 2008; 24: 595-603
        • Hotamisligil G.S.
        • Shargill N.S.
        • Spiegelman B.M.
        Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
        Science (New York, N.Y). 1993; 259: 87-91
        • Jellema A.
        • Plat J.
        • Mensink R.P.
        Weight reduction, but not a moderate intake of fish oil, lowers concentrations of inflammatory markers and PAI-1 antigen in obese men during the fasting and postprandial state.
        European Journal of Clinical Investigation. 2004; 34: 766-773
        • Neels J.G.
        • Olefsky J.M.
        Inflamed fat: what starts the fire?.
        The Journal of Clinical Investigation. 2006; 116: 33-35
        • Bouhlel M.A.
        • Derudas B.
        • Rigamonti E.
        • et al.
        PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.
        Cell Metabolism. 2007; 6: 137-143
        • Lumeng C.N.
        • Bodzin J.L.
        • Saltiel A.R.
        Obesity induces a phenotypic switch in adipose tissue macrophage polarization.
        The Journal of Clinical Investigation. 2007; 117: 175-184
        • Kaneko H.
        • Anzai T.
        • Horiuchi K.
        • et al.
        Tumor necrosis factor-alpha converting enzyme is a key mediator of abdominal aortic aneurysm development.
        Atherosclerosis. 2011; 218: 470-478
        • Menghini R.
        • Casagrande V.
        • Menini S.
        • et al.
        TIMP3 overexpression in macrophages protects from insulin resistance, adipose inflammation, and nonalcoholic fatty liver disease in mice.
        Diabetes. 2012; 61: 454-462
        • Casagrande V.
        • Menghini R.
        • Menini S.
        • et al.
        Overexpression of tissue inhibitor of metalloproteinase 3 in macrophages reduces atherosclerosis in low-density lipoprotein receptor knockout mice.
        Arteriosclerosis, Thrombosis, and Vascular Biology. 2012; 32: 74-81
        • Wang Y.
        • Sul H.S.
        Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation.
        Molecular and Cellular Biology. 2006; 26: 5421-5435
        • Gelling R.W.
        • Yan W.
        • Al-Noori S.
        • et al.
        Deficiency of TNFalpha converting enzyme (TACE/ADAM17) causes a lean, hypermetabolic phenotype in mice.
        Endocrinology. 2008; 149: 6053-6064
        • Serino M.
        • Menghini R.
        • Fiorentino L.
        • et al.
        Mice heterozygous for tumor necrosis factor-alpha converting enzyme are protected from obesity-induced insulin resistance and diabetes.
        Diabetes. 2007; 56: 2541-2546
        • Kaneko H.
        • Anzai T.
        • Horiuchi K.
        • et al.
        Tumor necrosis factor-alpha converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis.
        Circulation Journal. 2011; 75: 2482-2490
        • Menghini R.
        • Menini S.
        • Amoruso R.
        • et al.
        Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice.
        Gastroenterology. 2009; 136: 663-672 e664
        • Rask-Madsen C.
        • Dominguez H.
        • Ihlemann N.
        • et al.
        Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans.
        Circulation. 2003; 108: 1815-1821
        • Ciaraldi T.P.
        • Carter L.
        • Mudaliar S.
        • et al.
        Effects of tumor necrosis factor-alpha on glucose metabolism in cultured human muscle cells from nondiabetic and type 2 diabetic subjects.
        Endocrinology. 1998; 139: 4793-4800
        • Uysal K.T.
        • Wiesbrock S.M.
        • Marino M.W.
        • et al.
        Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function.
        Nature. 1997; 389: 610-614
        • Hotamisligil G.S.
        • Budavari A.
        • Murray D.
        • et al.
        Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha.
        The Journal of Clinical Investigation. 1994; 94: 1543-1549
        • Rui L.
        • Aguirre V.
        • Kim J.K.
        • et al.
        Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways.
        The Journal of Clinical Investigation. 2001; 107: 181-189
        • Plomgaard P.
        • Bouzakri K.
        • Krogh-Madsen R.
        • et al.
        Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation.
        Diabetes. 2005; 54: 2939-2945
        • Steinberg G.R.
        • Michell B.J.
        • van Denderen B.J.
        • et al.
        Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling.
        Cell Metabolism. 2006; 4: 465-474
        • de Alvaro C.
        • Teruel T.
        • Hernandez R.
        • et al.
        Tumor necrosis factor alpha produces insulin resistance in skeletal muscle by activation of inhibitor kappaB kinase in a p38 MAPK-dependent manner.
        The Journal of Biological Chemistry. 2004; 279: 17070-17078
        • Austin R.L.
        • Rune A.
        • Bouzakri K.
        • et al.
        siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle.
        Diabetes. 2008; 57: 2066-2073
        • Monroy A.
        • Kamath S.
        • Chavez A.O.
        • et al.
        Impaired regulation of the TNF-alpha converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans.
        Diabetologia. 2009; 52: 2169-2181
        • Cardellini M.
        • Menghini R.
        • Martelli E.
        • et al.
        TIMP3 is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SirT1.
        Diabetes. 2009; 58: 2396-2401
        • Su Z.
        • Tsaih S.W.
        • Szatkiewicz J.
        • et al.
        Candidate genes for plasma triglyceride, FFA, and glucose revealed from an intercross between inbred mouse strains NZB/B1NJ and NZW/LacJ.
        Journal of Lipid Research. 2008; 49: 1500-1510
        • Swindell W.R.
        Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse.
        BMC Genomics. 2009; 10: 585
        • Fiorentino L.
        • Vivanti A.
        • Cavalera M.
        • et al.
        Increased tumor necrosis factor alpha-converting enzyme activity induces insulin resistance and hepatosteatosis in mice.
        Hepatology (Baltimore, Md). 2010; 51: 103-110
        • Postic C.
        • Girard J.
        Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.
        The Journal of Clinical Investigation. 2008; 118: 829-838
        • Feldstein A.E.
        • Werneburg N.W.
        • Canbay A.
        • et al.
        Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.
        Hepatology (Baltimore, Md). 2004; 40: 185-194
        • Mato J.M.
        • Martinez-Chantar M.L.
        • Lu S.C.
        Methionine metabolism and liver disease.
        Annual Review of Nutrition. 2008; 28: 273-293
        • de Meijer V.E.
        • Le H.D.
        • Meisel J.A.
        • et al.
        Tumor necrosis factor alpha-converting enzyme inhibition reverses hepatic steatosis and improves insulin sensitivity markers and surgical outcome in mice.
        PloS One. 2011; 6: e25587
        • Fukumura D.
        • Ushiyama A.
        • Duda D.G.
        • et al.
        Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis.
        Circulation Research. 2003; 93: e88-97
        • Qi J.H.
        • Ebrahem Q.
        • Moore N.
        • et al.
        A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2.
        Nature Medicine. 2003; 9: 407-415
        • Murthy A.
        • Defamie V.
        • Smookler D.S.
        • et al.
        Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice.
        The Journal of Clinical Investigation. 2010; 120: 2731-2744
        • Swendeman S.
        • Mendelson K.
        • Weskamp G.
        • et al.
        VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling.
        Circulation Research. 2008; 103: 916-918
        • Horiuchi K.
        • Kimura T.
        • Miyamoto T.
        • et al.
        Cutting edge: TNF-alpha-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock.
        Journal of Immunology. 2007; 179: 2686-2689
        • Weskamp G.
        • Mendelson K.
        • Swendeman S.
        • et al.
        Pathological neovascularization is reduced by inactivation of ADAM17 in endothelial cells but not in pericytes.
        Circulation Research. 2010; 106: 932-940
        • Ashley E.A.
        • Ferrara R.
        • King J.Y.
        • et al.
        Network analysis of human in-stent restenosis.
        Circulation. 2006; 114: 2644-2654
        • Canault M.
        • Peiretti F.
        • Kopp F.
        • et al.
        The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: possible contribution to elevated plasma levels of soluble TNF alpha receptors.
        Atherosclerosis. 2006; 187: 82-91
        • Canault M.
        • Leroyer A.S.
        • Peiretti F.
        • et al.
        Microparticles of human atherosclerotic plaques enhance the shedding of the tumor necrosis factor-alpha converting enzyme/ADAM17 substrates, tumor necrosis factor and tumor necrosis factor receptor-1.
        The American Journal of Pathology. 2007; 171: 1713-1723
        • Donners M.M.
        • Wolfs I.M.
        • Olieslagers S.
        • et al.
        A disintegrin and metalloprotease 10 is a novel mediator of vascular endothelial growth factor-induced endothelial cell function in angiogenesis and is associated with atherosclerosis.
        Arteriosclerosis, Thrombosis, and Vascular Biology. 2010; 30: 2188-2195
        • Oksala N.
        • Levula M.
        • Airla N.
        • et al.
        ADAM-9, ADAM-15, and ADAM-17 are upregulated in macrophages in advanced human atherosclerotic plaques in aorta and carotid and femoral arteries–Tampere vascular study.
        Annals of Medicine. 2009; 41: 279-290
        • Johnson J.L.
        • Sala-Newby G.B.
        • Ismail Y.
        • et al.
        Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages.
        Arteriosclerosis, Thrombosis, and Vascular Biology. 2008; 28: 1647-1653
        • Dreymueller D.
        • Pruessmeyer J.
        • Groth E.
        • et al.
        The role of ADAM-mediated shedding in vascular biology.
        European Journal of Cell Biology. 2012; 91: 472-485
        • Furfaro A.L.
        • Sanguineti R.
        • Storace D.
        • et al.
        Metalloproteinases and advanced glycation end products: coupled navigation in atherosclerotic plaque pathophysiology?.
        Experimental and Clinical Endocrinology and Diabetes. 2012; 120: 586-590
        • George S.J.
        • Wan S.
        • Hu J.
        • et al.
        Sustained reduction of vein graft neointima formation by ex vivo TIMP-3 gene therapy.
        Circulation. 2011; 124: S135-S142
        • Reiss K.
        • Cornelsen I.
        • Husmann M.
        • et al.
        Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity.
        The Journal of Biological Chemistry. 2011; 286: 26931-26942
        • Blankenberg S.
        • Rupprecht H.J.
        • Bickel C.
        • et al.
        Circulating cell adhesion molecules and death in patients with coronary artery disease.
        Circulation. 2001; 104: 1336-1342
        • Pradhan A.D.
        • Rifai N.
        • Ridker P.M.
        Soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and the development of symptomatic peripheral arterial disease in men.
        Circulation. 2002; 106: 820-825
        • Ray K.K.
        • Morrow D.A.
        • Shui A.
        • et al.
        Relation between soluble intercellular adhesion molecule-1, statin therapy, and long-term risk of clinical cardiovascular events in patients with previous acute coronary syndrome (from PROVE IT-TIMI 22).
        The American Journal of Cardiology. 2006; 98: 861-865
        • Horiuchi T.
        • Mitoma H.
        • Harashima S.
        • et al.
        Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents.
        Rheumatology (Oxford). 2010; 49: 1215-1228
        • Richards F.M.
        • Tape C.J.
        • Jodrell D.I.
        • et al.
        Anti-tumour effects of a specific anti-ADAM17 antibody in an ovarian cancer model in vivo.
        PloS One. 2012; 7: e40597
        • Milne J.C.
        • Lambert P.D.
        • Schenk S.
        • et al.
        Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
        Nature. 2007; 450: 712-716
        • Murphy G.
        • Murthy A.
        • Khokha R.
        Clipping, shedding and RIPping keep immunity on cue.
        Trends in Immunology. 2008; 29: 75-82
        • Menge T.
        • Zhao Y.
        • Zhao J.
        • et al.
        Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury.
        Science Translational Medicine. 2012; 4: 161ra150
      1. Fiorentino L. Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. Embo Molecular Medicine, in press.

        • Monteleone I.
        • Federici M.
        • Sarra M.
        • et al.
        Tissue inhibitor of metalloproteinase-3 regulates inflammation in human and mouse intestine.
        Gastroenterology. 2012; 143 (e1271–1274): 1277-1287