ReviewThe role of ADAM17 in metabolic inflammation
Introduction
The TNF-alpha Converting Enzyme (TACE), also called ADAM17 (A Disintegrin and A Metalloproteinase 17) is a type I transmembrane protein that belongs to a superfamily of Zn dependent metalloproteases. ADAM17 plays a key role in the regulation of the proteolytic release from cellular membranes of some cytokines, chemokines, growth factors and their receptors, including TNF-α, TNF receptors I and II, TGF-α, l-selectin, IL-6, and M-CSF receptor 1, affecting downstream signaling and cellular responses (Table 1) [1]. Increased ADAM17-mediated shedding has been described in a variety of diseases such as ischemia, heart failure, arthritis, atherosclerosis, diabetes, cancer, neurological and immune diseases [2]. The major pro-inflammatory cytokine processed by ADAM17 is TNF-α which is produced by a number of cell types including macrophages, monocytes, T-cells, and plays a crucial role in the pathogenesis of inflammation [3]. Recently, it has been pointed out that exclusively the extracellular domains of ADAM17 are needed for interaction with its substrates [4].
Tissue Inhibitor of MetalloProteinase 3 (TIMP3), a key endogenous inhibitor involved in regulation of the activity of Matrix Metalloproteinases (MMPs) and ADAMs, is the only known physiological inhibitor of ADAM17 (Fig. 1). ADAM17 and TIMP3 have parallel baseline expression patterns in murine organs during development [5]. Down-regulation of TIMP3 increases ADAM17 activity while up-regulation of TIMP3 inhibits ADAM17 activity. Recent evidence indicates that cell surface presentation of ADAM17 is crucial for the regulation of its shedding activity [6]. ERK or p38 MAPK signaling changes the dynamic balance between ADAM17 dimers and monomers and their conformations, presumably as a result of changes in phosphorylation of its cytoplasmic domain, which is required for ADAM17 dimerization [6]. In the absence of MAPK stimulation, ADAM17 is presented as dimers at the cell surface, allowing TIMP3 to efficiently interact with and inhibit ADAM17, whereas the activation of ERK or p38 MAPK signaling, which leads to ADAM17 activation, results in increased monomer presentation and release of TIMP3 from ADAM17 [6]. Recently, iRhom2, a molecule belonging to a class of polytopic endoplasmic reticulum proteins, has been identified as an essential factor for the activity and trafficking of ADAM17, through its interaction with both endogenous full length and the mature form of ADAM17 [7], [8].
Previous reports have implicated the ADAM17/TIMP3 dyad as a mediator between metabolic stimuli and innate immunity. TIMP3 deficient mice have shown increased levels of TNF-α and severity of inflammation [9]. Interestingly, a genetic transmission of TIMP3 deficiency is able to impair glucose tolerance [10]; TIMP3 was found downregulated in adipose tissue of genetic models of obesity [11] and in circulating monocyte cells from human subjects with risk for diabetes and atherosclerosis [12]. Here we review the most recent findings on ADAM17 activation as a consequence of loss of TIMP3 in the context of Metabolic Syndrome (Fig. 2).
Section snippets
ADAM17 role in adipose tissue inflammation
The adipose tissue is a regulatory organ that, through a deregulated release of free fatty acids, adhesion molecules and inflammatory cytokines plays a key role in the obesity-associated complications such as dyslipidemia, insulin resistance and type 2 diabetes as well as the low-grade inflammation and increased risk of cardiovascular disease [13].
TNF-α was the first cytokine recognized as a link between obesity, inflammation and diabetes. TNF-α appears to be a crucial contributor to adipokine
TACE/ADAM17 in skeletal muscle insulin resistance
TNF-α has been shown to impair glucose uptake from skeletal muscle both in vivo and in vitro [27], [28], [29]. A negative effect of TNF-α on insulin signaling and glucose uptake has been demonstrated both at insulin receptor and post-receptor level including direct and indirect inhibition of insulin receptor tyrosine kinase [30], serine phosphorylation of Insulin Receptor Substrate 1 [31], inhibition of AKT substrates [32], suppression of AMPK activity [33], and activation of inhibitor of kappa
TACE/ADAM17 in hepatic insulin resistance and steatosis
Recent findings showed that the ADAM17/TIMP3 dyad plays a central role in the development and progression of non-alcoholic fatty liver disease (NAFLD) [26], [40]. The contribution of insulin resistance to the development of fatty liver occurs in part by deficient control of lipid storage in white adipose tissue and in part by altered control of hepatic lipogenesis and mitochondrial fatty acid oxidation [41]. TNF-α is among the cytokines involved in linking nutrient availability to inflammation
Future directions and therapeutical perspectives
Recent works pinpoint the role of the ADAM17-TIMP3 dyad in spatial regulation of TNF-α activity in major metabolic tissues. Many data suggest that ADAM17 is activated in metabolic disorders and contributes to progressive deterioration of metabolic homeostasis via regulation of pathways involved in adipose tissue infiltration by macrophages, reduction of glucose uptake in skeletal muscle and increased lipogenesis in liver. Altogether these actions promote the progression of insulin resistance
Acknowledgments
This study was in part supported by the following grants: Juvenile Diabetes Research Foundation Regular Research 1-2007-665, Telethon GGP08065, Fondazione Roma 2008, FP7-Health-241913 FLORINASH, FP-7 EURHYTHDIA, and PRIN 2009FATXW3_002 (all to M.F.)
References (70)
- et al.
ADAM17: a molecular switch to control inflammation and tissue regeneration
Trends in Immunology
(2011) - 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) - et al.
Expression analysis of the entire MMP and TIMP gene families during mouse tissue development
FEBS Letters
(2004) - et al.
Tissue inhibitor of metalloproteinases 3 regulates resolution of inflammation following acute lung injury
The American Journal of Pathology
(2010) - et al.
Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation
The Journal of Biological Chemistry
(2003) - et al.
PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties
Cell Metabolism
(2007) - et al.
Tumor necrosis factor-alpha converting enzyme is a key mediator of abdominal aortic aneurysm development
Atherosclerosis
(2011) - et al.
Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling
Cell Metabolism
(2006) - 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) - 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)
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
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
The role of ADAM-mediated shedding in vascular biology
European Journal of Cell Biology
Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity
The Journal of Biological Chemistry
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
Clipping, shedding and RIPping keep immunity on cue
Trends in Immunology
An essential role for ectodomain shedding in mammalian development
Science (New York, N.Y)
Cutting edge: a dominant negative form of TNF-alpha converting enzyme inhibits proTNF and TNFRII secretion
Journal of Immunology
TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association
Science Signaling
iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS
Science (New York, N.Y)
Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE
Science (New York, N.Y)
Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha
The Journal of Clinical Investigation
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
Inflamed adipose tissue, insulin resistance and vascular injury
Diabetes/metabolism Research and Reviews
Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance
Science (New York, N.Y)
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
Inflamed fat: what starts the fire?
The Journal of Clinical Investigation
Obesity induces a phenotypic switch in adipose tissue macrophage polarization
The Journal of Clinical Investigation
TIMP3 overexpression in macrophages protects from insulin resistance, adipose inflammation, and nonalcoholic fatty liver disease in mice
Diabetes
Overexpression of tissue inhibitor of metalloproteinase 3 in macrophages reduces atherosclerosis in low-density lipoprotein receptor knockout mice
Arteriosclerosis, Thrombosis, and Vascular Biology
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
Deficiency of TNFalpha converting enzyme (TACE/ADAM17) causes a lean, hypermetabolic phenotype in mice
Endocrinology
Mice heterozygous for tumor necrosis factor-alpha converting enzyme are protected from obesity-induced insulin resistance and diabetes
Diabetes
Tumor necrosis factor-alpha converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis
Circulation Journal
Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice
Gastroenterology
Cited by (87)
Burden of cardiometabolic risk factors and vascular health
2024, American Heart JournalOptimization of fluorescent substrates for ADAM17 and their utility in the detection of diabetes
2023, Analytical BiochemistryOld known and possible new biomarkers of ANCA-associated vasculitis
2022, Journal of AutoimmunityCOVID-19–Associated Endothelial Dysfunction and Microvascular Injury: From Pathophysiology to Clinical Manifestations
2022, Cardiac Electrophysiology ClinicsCA.ME.LI.A. An epidemiological study on the prevalence of CArdiovascular, MEtabolic, LIver and Autoimmune diseases in Northern Italy
2021, Nutrition, Metabolism and Cardiovascular DiseasesMolecular Determinants Involved in the Docking and Uptake of Tumor-Derived Extracellular Vesicles: Implications in Cancer
2024, International Journal of Molecular Sciences