Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases Kyunghee Byun, YongCheol Yoo, Myeongjoo Son, Jaesuk Lee, Goo-Bo Jeong, Young Mok Park, Ghasem Hosseini Salekdeh, Bonghee Lee PII: DOI: Reference:
S0163-7258(17)30044-X doi:10.1016/j.pharmthera.2017.02.030 JPT 7038
To appear in:
Pharmacology and Therapeutics
Please cite this article as: Byun, K., Yoo, Y.C., Son, M., Lee, J., Jeong, G.-B., Park, Y.M., Salekdeh, G.H. & Lee, B., Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases, Pharmacology and Therapeutics (2017), doi:10.1016/j.pharmthera.2017.02.030
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P&T 23054
Advanced glycation end-products produced systemically and by macrophages : a common contributor to inflammation and degenerative
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diseases
Kyunghee Byun1,2, ¶, YongCheol Yoo3,¶, Myeongjoo Son2, Jaesuk Lee1, Goo-Bo Jeong2, Young Mok Park3,*, Ghasem Hosseini Salekdeh4,*, Bonghee Lee1,2,*
Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon
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1
University, Incheon 406-840, Republic of Korea
Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine,
Incheon 406-799, Republic of Korea 3
Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 305-811,
Republic of Korea
Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute
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Corresponding authors:
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for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Bonghee Lee, DVM, PhD Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea Tel: +82 32 899 6582, Fax: +82 32 899 6519 E-mail:
[email protected] Young Mok Park, PhD Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34047, Republic of Korea Tel: +82 42 865 3420, FAX: +82 42 865 3419 E-mail:
[email protected] Ghasem Hosseini Salekdeh, PhD Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran Tel: +98 21 22306485, Fax: +98 21 23562507 E-mail:
[email protected] * , ¶ These
authors contributed equally to this work.
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ABSTRACT
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Advanced glycation end products (AGEs) and their receptor have been implicated in the
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progressions of many intractable diseases, such as diabetes and atherosclerosis, and are also critical for pathologic changes in chronic degenerative diseases, such as Alzheimer’s disease,
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Parkinson’s disease, and alcoholic brain damage. Recently activated macrophages were found to be a source of AGEs, and the most abundant form of AGEs, AGE-albumin excreted by macrophages has been implicated in these diseases and to act through common pathways.
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AGEs inhibition has been shown to prevent the pathogenesis of AGEs-related diseases in human, and therapeutic advances have resulted in several agents that prevent their adverse
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effects. Recently, anti-inflammatory molecules that inhibit AGEs have been shown to be good candidates for ameliorating diabetic complications as well as degenerative diseases.
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This review was undertaken to present, discuss, and clarify current understanding
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regarding AGEs formation in association with macrophages, different diseases, therapeutic
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and diagnostic strategy and links with RAGE inhibition.
Keywords: Advanced Glycation End products (AGEs), Receptor for AGEs (RAGE),
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macrophage, inflammation, degenerative diseases
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Table of Contents
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1. Introduction----------------------------------------------------------- 5 2. Advanced glycation end-products (AGEs)-------------------- 5
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3. Receptors for AGEs ------------------------------------------------- 7
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4. Macrophage activation mediators and AGEs formation--- 10 5. Development of therapeutics against AGEs ----------------- 15
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6. Conclusion and future perspectives---------------------------- 18
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Conflict of interest statement-------------------------------------- 19
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Acknowledgments--------------------------------------------------- 19
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References-------------------------------------------------------------- 20
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Abbreviations
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AD, Alzheimer’s disease; ADMA, asymmetric dimethylarginine; AGEs, advanced glycation end products; AFLD, alcoholic fatty liver disease; ALI, acute lung injury; ALS, amyotrophic lateral sclerosis; AMI, acute myocardial infarction; APP, acute phase protein; Aβ, amyloid
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beta; Bax, BCL2 associated X, apoptosis regulator; CaMKKβ, calcium/calmodulin-dependent
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protein kinase kinase beta; CCL3, chemokine (C-C motif) ligand 3; CCL4, chemokine (C-C motif) ligand 4; CD36, cluster of differentiation 36; CKD, chronic kidney disease; CMA, N(omega)-carboxymethylarginine; CML, N(6)-carboxymethyllysine; COPD, chronic obstructive pulmonary disease; CTGF, connective tissue growth factor; CVDs, cardiovascular diseases; DAMPs, damage-associated molecular pattern molecules; DN, diabetic nephropathy; EGCG, epigallocatechin gallate; Egr-1, early growth response-1; ERK1/2, extracellular signal-regulated kinase 1/2; FEEL-1, fasciclin EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-1; FEEL-2, fasciclin EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-2; HDL, high-density lipoprotein; HMGB1, high mobility group protein B1; HUVEC, human umbilical vein
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endothelial cell; IL-6, interleukin-6; IL-10, interleukin-10; IL-1β, interleukin-1 beta; INF-γ, interferon gamma; IPF, idiopathic pulmonary fibrosis; JAK, janus kinase; JNK, c-Jun Nterminal kinase; Lox-1, lectin-like oxidized low-density lipoprotein receptor 1; LPS, lipopolysaccharide; Mac-1, macrophage-1 antigen; MAPK, mitogen activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; MMP-13, matrix metalloproteinase 13; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; NO, nitric oxide; NOS, nitric oxide synthases; OA, osteoarthritis; PAR, protease-activated receptor; PAR1, protease-activated receptor 1; PAR2, proteaseactivated receptor 2; PAR3, protease-activated receptor 3; PAR4, protease-activated receptor 4; PD, Parkinson’s disease; PDGF, platelet-derived growth factor; PG, prostaglandin; PGE2,
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prostaglandin E2; PPAR-α, peroxisome proliferator activated receptor-alpha; PPAR-γ, peroxisome proliferator-activated receptor gamma; RA, rheumatoid arthritis; Rac2, rasrelated C3 botulinum toxin substrate 2; RAGE, receptor for advanced glycation endproducts; ROS, reactive oxygen species; S100A8, S100 calcium binding protein A8; S100A9, S100 calcium binding protein A9; S100A12, S100 calcium binding protein A12; SAPK, stressactivated protein kinase; SCI, spinal cord injury; sRAGE, soluble RAGE; SR-BI, scavenger receptor class B type I; SR-BII, scavenger receptor class B type II; STAT, signal transducer and activator of transcription; STAT1, signal transducer and activator of transcription 1; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor
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1. Introduction
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Advanced glycation end products (AGEs) have long been considered potent toxic molecules
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that promote host cell death and contributing to organ damage in man. AGEs can induce the
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development or progression of not only diabetic complications but the pathophysiologies of many diseases, including cardiovascular diseases (CVDs) and neurodegenerative diseases like Alzheimer's disease (AD), Parkinson’s disease (PD), and alcoholic brain damage (Yan et
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al., 2007; Simm et al., 2007; Srikanth et al., 2011; Byun et al., 2012, 2014; Bayarsaikhan et al., 2016). AGEs bind with their receptor RAGE (receptor for advanced glycation end products), which is highly expressed during host cell death through reactive oxygen species (ROS) and
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strong activations of extracellular signal-regulated kinase 1/2 (ERK1/2) ERK1/2 and nuclear factor kappa B (NF-κB) pathways in many diseases. (Teismann et al., 2012; Wang et al., 2013,
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2014). Inhibition of AGEs from blood or activated macrophages had been well shown to
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decrease the pathogenesis of several diseases and several agents have been developed to ameliorate their adverse effects. Anti-inflammatory molecules that inhibit AGEs may be
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good candidate treatments for diabetic complications and degenerative diseases. In this review, we discuss the formation of AGEs and RAGE, their association with the mononuclear phagocytic system in diseases, the current therapeutic agents used and their
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adverse effects, and finally we suggest a strategy for targeting macrophage AGEs and RAGE interaction for possible drug target.
2. Advanced glycation end-products (AGEs)
AGEs are a heterogeneous group of irreversible products resulting from nonenzymatic glycation and oxidation of proteins, nucleic acids, and lipids (Singh et al., 2001; Goldin et al., 2006). Glycation produces AGEs compounds with toxic properties associated with inflammation and oxidative stress (Takeuchi & Yamagishi, 2004). AGEs accumulate in the extra cellular matrix of various tissues and critically contribute to chronic diseases (Bierhaus et al., 1998; Tessier et al., 1999). Furthermore, AGEs have been shown to become antigenic, and thus, to induce immune responses (Ge et al., 2005; Kurien & Scofield, 2008). AGEs also
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have adverse effects on cellular functions by cross-linking intracellular and extracellular proteins, which trigger diverse diseases, such as arthritis, neurological disorders, cancers,
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diabetes and cardiovascular disorders, (Jono et al., 2002; Abe et al., 2004; Ryan et al., 2014;
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Russo & Frangogiannis, 2016) (Fig. 1).
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2.1 Intracellular formation and the toxic properties of AGEs
2.1.1 Formation of AGEs
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AGEs are formed by glycation, which is a nonenzymatic reaction between ketones or aldehydes and the amino groups of various proteins and contributes to protein aging
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(Gkogkolou & Böhm, 2012; Ramasamy et al., 2012). Protein glycation occurs in both normal and hyperglycemic condition, and forms irreversible AGEs. This process begins with the conversion of reversible Schiff base adducts to more stable, covalently-bound Amadori
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rearrangement products and finally the Maillard reaction (Ansari & Dash, 2013; Ott et al.,
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2014). AGEs are also formed in the absence of hyperglycemia by homeostatic imbalances,
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such as redox imbalances (Limongi & Baldelli, 2016), aging (Karumanchi et al., 2015), kidney disease (Arsov et al., 2014), or autoimmune diseases (Nienhuis et al., 2009). In addition, AGEs are derived from foods (e.g. milk, meat, coffee, cheese), especially those prepared
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under high temperature conditions, stored for long periods, or with food additives (Luevano-Contreras & Chapman-Novakofski, 2010).
2.1.2 Toxic properties of AGEs Elevated levels of AGEs support the formations of reactive oxygen and nitrogen species which in turn induce further AGEs formation. AGEs induce oxidative stress by activating RAGE, which results in mitochondrial dysfunction (Ward et al., 2013; Lane et al., 2015). Under oxidative stress, mitochondrial Ca2+ accumulation leads to a cell death signal (Mahali et al., 2011), and AGEs excreted by activated macrophages also induce mitochondrial dysfunction and cell death. Extensive studies have demonstrated mitochondrial dysfunction is an important factor in the pathogenesis of AD (Aliev et al., 2010), alcoholic fatty liver disease (AFLD) (Song et al., 2014), diabetes (Rolo & Palmeira, 2006), and chondrocyte degeneration (Blanco et al., 2004) (Fig. 2).
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3. Receptors for AGEs AGEs can interact with two types of cell surface receptors. Scavenger receptors are
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predominantly involved in AGEs capture, removal and degradation. This group of receptors
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includes type I and type II macrophage scavenger receptors, cluster of differentiation 36
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(CD36), fasciclin EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-1 (FEEL-1) and fasciclin EGF-like, laminin-type EGF-like, and link domaincontaining scavenger receptor-2 (FEEL-2), scavenger receptor class B type I (SR-BI) and
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scavenger receptor class B type II (SR-BII), and lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1) (Miyazaki et al., 2002; Ott et al., 2014). The other type of AGEs receptor,
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RAGE initiates specific cellular signaling events in response to AGEs exposure. RAGE is a member of immunoglobulin (Ig) superfamily, and binds multi-ligands like AGEs (Huttunen et al., 1999), high mobility group protein B1 (HMGB1) (Dhumale et al., 2015), S100 (Donato, (Stern et al., 2002), amphoterin, and calgranulins, and then activate several
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2007), A
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condition-dependent cellular pathways (Li et al., 2004). RAGE is expressed in various tissues including brain, heart, liver, lung, kidney, and cartilage and it plays an important role in
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disease progression. Expression level of RAGE is minimal under normal conditions but increases in disease states, such as AD, PD, alcoholic brain damage, vascular disease, diabetes, acute myocardial infarction (AMI), chronic kidney disease (CKD), hepatic fibrosis,
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chronic obstructive pulmonary disease (COPD), and inflammatory disease, which may be the result of cell damage caused by the overproductions of ROS, cytokines, and proinflammatory molecules (Fig. 3, Supplementary Table 1).
3.1 Intracellular signaling pathway of RAGE in disease: AGEs dependent RAGE expression is well documented in many diseases. The signaling pathways downstream of RAGE are similar and eventual lead to mitochondrial dysfunction and cell death. The detailed summary is provided below and in Figure 3 and Supplementary Table 1. 3.1.1 Relations between RAGE and Neuronal death RAGE is highly expressed on neurons during neurodegenerative processes, such as AD, PD, stroke, alcoholic brain damage, and amyotrophic lateral sclerosis (ALS). In the presence of
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inflammation, binding of AGEs to RAGE strongly induces the activations of the NF-κB pathways (Teismann et al., 2012; Wang et al., 2013, 2014). Furthermore, the interaction
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between AGE-albumin and RAGE induces neuronal cell death through stress-activated
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protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)/BCL2 associated X, apoptosis regulator (Bax) in AD (Byun et al., 2012a) and the SAPK/JNK/p38 pathway in the alcoholic
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brain damage (Byun et al., 2014). Furthermore, increased HMGB1 binding with RAGE can cause neuronal cell death through NF-κB activation in stroke and AD (Wang et al., 2010; Bortolotto & Grilli, 2016). S100 protein induces neuronal cell death through the NF-κB/tumor
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necrosis factor alpha (TNF- pathway in PD (Sathe et al., 2012; Abdelsalam & Safar, 2015), and in AD, binding of Ato RAGE also leads to neurodegeneration and neuronal cell death
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through p21ras, ERK1/2, p38, SAPK/JNK, phosphoinositol-3 kinase, and the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway (Origlia et al., 2010;
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3.1.2 Cardiomyocytes and RAGE
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Son et al., 2012).
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RAGE expression of cardiomyocytes is increased in acute myocardial infarction by AGEs, HMGB1 and S100, and these proteins induce cell death via activation of the MAPK pathway
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(Aleshin et al., 2008; Andrassy et al., 2008; Tsoporis et al., 2010).
3.1.3 Hepatocytes and RAGE Binding of AGEs to RAGE strongly induces the phosphorylation of uncoupling protein-2 (UCP-2) and ATP synthesis (Kuhla et al., 2011). HMGB1 released from damaged hepatocyte after injury interacts with RAGE and leads to hepatic fibrosis by activating SMAD2 and phosphorylating ERK1/2 (Kao et al., 2014) or JNK/ERK1/2 during early growth response-1 (Egr-1) (Zeng et al., 2009).
3.1.4 Alveolar epithelial cells and RAGE The RAGE binding with AGEs and HMGB1 has been well described in idiopathic pulmonary fibrosis (IPF). Binding of AGEs and RAGE inhibits TGF- induced ERK1/2 and SMAD phosphorylation (Song et al., 2011) and up-regulates Egr-1, which also activates RAGE transcription in COPD (Reynolds et al., 2008b). In addition, the interaction between
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HMGB1 and RAGE leads to alveolar disruption and fibrosis due to the activation of TGF-
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via the productions of platelet-derived growth factor (PDGF) in IPF (He et al., 2007).
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3.1.5 Renal tubular epithelial cells and RAGE
Interaction between AGEs and RAGE stimulates oxidative stress and promotes diabetic
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nephropathy (DN) progression. Importantly, AGE-RAGE acts to the mitogen activated protein kinase (MAPK)/NF-κB and protein kinase C signaling pathway (Yamagishi & Matsui, 2010) or promote to connective tissue growth factor (CTGF) and TGF- during
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inflammation and fibrotic process (Cheng et al., 2015a). Up-regulation of HMGB1 binding to RAGE provokes inflammatory reactions via ERK1/2- NF-kB signaling, which turn on
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transcription of TNF-, interleukin-6 (IL-6), chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 4 (CCL4) and C-X-C motif chemokine 12 (CXCL12) in DN and
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3.1.6 Chondrocytes and RAGE
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enhances asymmetric dimethylarginine (ADMA) in CKD (Nakamura et al., 2009).
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The binding AGEs to RAGE activate the JNK/p38, peroxisome proliferator-activated receptors alpha (PPAR-α) and NF-κB signaling pathway and these signaling pathways associated with inflammatory and oxidative responses in osteoarthritis (OA). Furthermore,
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high levels of HMGB1 have been reported in the synovial fluid of arthritis patients (Kokkola et al., 2002), and the interaction between HMGB1 and RAGE induces the expressions of TNF- and interleukin 1 beta (IL-1) on chondrocytes (Terada et al., 2011). Furthermore, when the expression of S100 calcium binding protein A12 (S100A12) and A4 (S100A4) is increased and it stimulates inflammation and degeneration via the RAGE mediated MAPK, NF-κB and MMP-13/vascular endothelial growth factor (VEGF)/p38 and NF-κB signaling pathway in OA (Yammani et al., 2009; Nakashima et al., 2012).
4. Mediators of macrophage activation and AGE formation
The macrophages originate from bone marrow and then migrate and circulate in different tissues, such as brain, liver, heart, kidney, and cartilage (Kraft & Harry, 2011; Varol et al.,
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2015). Activated macrophages often induce inflammatory degeneration of host cells or dysfunction in AD, PD, stroke, vascular disease, and inflammatory diseases. Macrophages
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are activated by exposure to various stimuli, such as cytokines, proteases, prostaglandins
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(PGs), nitric oxide (NO), free radicals or RAGE ligands, including A, AGEs, HMGB1 and
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lipopolysaccharide (LPS), under pro- and inflammatory conditions (Fig. 4).
4.1 Cytokines
Cytokines are involved in systemic inflammation and degenerative diseases. They can be
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released by neurons, cardiomyocytes, hepatocytes, alveolar epithelial cells, neutrophils, eosinophils, or mast cells at various levels when cells are stimulated or in the presence of
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disease conditions. These cytokines such as α-synuclein (Kim & Joh, 2006), Chromogranin A (Heneka et al., 2010), Interferon gamma (INF-γ) (Gensel & Zhang, 2015) were well reported
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as activating macrophages under disease conditions.
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4.2 Proteases
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Serine proteases cleave their receptors to modulate important biological processes including host defense, chemotaxis, cytokine and growth factor release, vascular function, tissue repair, apoptosis, inflammation and immune response (Steinhoff et al., 2005). Protease-activated
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receptors (PARs) compose a subfamily of G protein-coupled receptors with seven transmembrane receptors that couple to guanosine-nucleotide-binding proteins (Brass & Molino, 1997). The PAR family has four members, namely, protease-activated receptor 1 (PAR1), protease-activated receptor 2 (PAR2), protease-activated receptor 3 (PAR3), and protease-activated receptor 4 (PAR4), and of these, PAR2 can modulate the activities of various cells, including epithelial cells, smooth muscle cells, endothelial cells, and macrophages in a variety of tissues (Nystedt et al., 1996; Steinhoff et al., 2005).
4.3 Prostaglandins (PGs) PGs act as critical regulators during the initiation of inflammatory processes. PG expressions are significantly increased in infected tissues, and contribute to the development of the principal signs of the acute inflammatory phase (Ricciotti & FitzGerald, 2011). Prostaglandin
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E2 (PGE2) is one of the most abundant PGs and exhibits variable biological activities, which include the regulations of blood pressure, gastrointestinal integrity, and immune response
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(Legler et al., 2010).
4.4 Acute phase proteins (APPs)
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APPs response to inflammation may be an increase (positive acute-phase proteins, APPs) or decrease (negative APPs) in plasma concentration (Gruys et al., 2005). Positive APPs are involved in different physiological functions in the immune system. For example,
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haptoglobin acts to inhibit or prevent microbe growth and alpha 2 macroglobulin and serpins provide negative feedback on the inflammatory processes (Jain et al., 2011).
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Some of these proteins act to inhibit or prevent microbe growth, while others modulate negative feedback from inflammatory processeswhich include albumin, transferrin,
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transthyretin, transcortin, retinol-binding protein and anti-thrombin (Ritchie et al., 1999;
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Gruys et al., 2005).
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4.5 Nitric oxide and free radicals 4.5.1 Nitric oxide (NO)
NO is a free radical and an important cellular signaling mediator related to various
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pathological and physiological processes, including the modulation of blood pressure, neurotransmission, and of macrophage cytotoxicity. NO is synthesized by nitric oxide synthase (NOS) from oxygen and NADPH as cofactor of NOS (Mayer et al., 1990). NO is well known as endogenous mediator during vasodilator inflammatory processes (Wallace, 2005).
4.5.2 Oxidative stress In oxidative stress, greater amounts of oxygen free radicals are found under disease states or after exposure to toxic agents and are increased by environmental stresses such as UV or heat. Oxidative stress elevates the expressions of inflammatory mediators, which induce macrophage activation in the presence of inflammation (Macdonald et al., 2003), AMI (Di Filippo et al., 2006), COPD (Rahman, 2005), OA (Ziskoven et al., 2010) and
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neurodegenerative disease, such as AD (Zhu et al., 2004), PD (Dias et al., 2013).
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4.6 RAGE ligands
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RAGE ligands including A, AGEs, HMGB1, LPS, macrophage-1 antigen (Mac-1), phosphatidylserine and S100 also modulate important biological processes required for
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macrophage activation (Hofmann et al., 1999; Schmidt et al., 2001; Chavakis et al., 2004; He et al., 2011). The various types of RAGE ligands that induce macrophage activation in degenerative diseases are summarized in Table 1. A is cleaved from amyloid precursor
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protein and is the main cause of AD, a major component of amyloid plaque (Fang et al., 2010). Nuclear HMGB1 regulates pro-inflammatory factors, and HMGB1 can be released by
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neurons in the damaged brain (Fang et al., 2010). HMGB1 up-regulation leads to microglial activation in many diseases including alcoholic brain damage (Crews & Vetreno, 2014; 2016),
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stroke (Liesz et al., 2015; Xiong et al., 2016), spinal cord injury (SCI) (Kikuchi et al., 2011),
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AMI (Herzog et al., 2014) and acute lung injury (ALI) (Deng et al., 2013). LPS can stimulate macrophages and monocytes to secrete various inflammatory mediators, including IL-6
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(Hirohashi & Morrison, 1996). LPS also induces macrophage activation in SCI (Xie et al., 2004), hypertension (Hernanz et al., 2004), ALI (Zhu et al., 2013), liver cirrhosis (Jirillo et al., 2002), IPF (Freeburn et al., 2005), and COPD (Miles et al., 1999). S100 members also activate
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macrophages, and are also secreted by activated macrophages (Donato, 1999).
4.7. Proteomic analysis of activated macrophages To further understand the molecular mechanism responsible for macrophage activation, proteomic studies have been recently conducted in a variety of disease models, including neurodegenerative disease (Zhou et al., 2005; Reynolds et al., 2008a; Ma et al., 2013; Yoo et al., 2015), acute lung injury/acute respiratory distress syndrome (Dong et al., 2013), kidney stone disease (Singhto et al., 2013), metabolic diseases (Freiwald et al., 2013; Kratz et al., 2014), cancer (Kobayashi et al., 2009; Zhu et al., 2015), atherosclerosis (Kang et al., 2006; Burillo et al., 2009), and virus infections (Lietzén et al., 2011; Miettinen et al., 2012). The proteins secreted by activated macrophages are being actively investigated in terms of their abilities to damage or protect tissues.
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4.7.1 Secretome analysis of activated macrophages
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The most dramatically inducible proteins secreted by activated macrophages are
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inflammatory molecules, such as cytokines and chemokines. Among cytokines, surprisingly, various types of RAGE ligands, such as AGEs (most abundantly in albumin), HMGB1 and
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S100 proteins, are secreted by activated macrophages. HMGB1 and S100 protein are damage-associated molecular pattern molecules (DAMPs) that are released by damaged and stressed cells. DAMPs, which are also called alarmins or danger signals, are host-derived
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endogenous molecules that can trigger immune response, and are recognized by DAMP receptors, which include RAGE (Saïd-Sadier & Ojcius, 2012).
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HMGB1 can be released from necrotic or damaged cells or by activated immune cells, and regulates endothelial cell activation, cell migration, inflammation, proliferation, and differentiation (Bertheloot & Latz, 2016; Saïd-Sadier & Ojcius, 2012). In post-ischemic brains,
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HMGB1 was found to be induced in and secreted by activated microglia (Kim et al., 2008;
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Kim et al., 2012; Shin et al., 2014). Interestingly, the release and translocation of HMGB1 in
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macrophages was observed to be inhibited by various molecules that can reduce inflammation and mortality in sepsis models (Hagiwara et al., 2009; Ye et al., 2012; Zhang et al., 2014; Zhou et al., 2014; Cheng et al., 2015b; Kim et al., 2015; Elfeky et al., 2016). HMGB1
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secretion was also significantly increased by macrophages in the presence of chronic inflammation diseases and in models of atherosclerosis (Kalinina et al., 2004), COPD (Mortaz et al., 2015), rheumatoid arthritis (RA) (Zetterström et al., 2008), and renal tubuleinterstitial fibrosis (Tian et al., 2015). The S100 protein family is composed of approximately 25 proteins (Gross et al., 2014), and among them, S100A8 and S100 calcium binding protein A9 (S100A9) are often found abundantly in macrophages (Rammes, 1997; Xu & Geczy, 2000; Xu et al., 2001; McCormick et al., 2005; Farris et al., 2011). These two proteins are also released by activated macrophages in patients with inflammatory muscle diseases, and induced myoblast apoptosis via caspase 3 activation (Seeliger et al., 2003).
4.7.2 Albumin and AGE-albumin synthesis in macrophages The liver is known as responsible for production of albumin in body, however there are also reports of non-hepatic origins. These include pancreas, kidney (Nahon et al., 1988), skeletal
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muscle (Müller & Heizmann, 1982; Kobayashi & Tashima, 1990), thyroid gland (de Vijlder et al., 1992). Activated macrophages are also known as alternate source which include
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microglial cells in AD (Byun et al., 2012a; 2012b), Alcoholic brain damages (Byun et al., 2014)
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and PD (Bayarsaikhan et al., 2016).
Macrophage activation leads to the release RAGE ligands, including AGEs, HMGB1,
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amyloid beta (Aβ) and pro-inflammatory cytokines, which at elevated levels damage host cells. These ligands are released during inflammation or injury and this leads to the up-
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regulation of RAGE on host cells such as neurons (Borsi et al., 2012). Binding of AGEs to RAGE releases IL- β and TNF-α in AD (Fang et al., 2010), and in PD regulates the
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expressions of pro-inflammatory cytokines and activates of MAPK, NF-κB, and IFN-γ (Kim & Joh, 2006). Furthermore in AD, Aβ interacts with AGEs and induces microglial activation and neuroinflammation via ERK1/2 and NF-κB activation (Lv et al., 2014). Several authors
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have demonstrated AGEs accumulation in the brains of patients with AD (Ahn et al., 2008)
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or alcoholic brain damage (Byun et al., 2014). In addition, Aβ stimulated human microglial cells significantly synthesize and release more albumin (Ahn et al., 2008), and abundant
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quantities of AGE-albumin, a new RAGE ligand (Byun et al., 2012a). Aβ plaques are colocalized with AGE-albumin in Aβ1-42 injected rat and human AD brain (Byun et al., 2012b) and the AGE-albumin induces calcium influx via up-regulation of RAGE, and this leads to
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neuronal death in AD (Byun et al., 2012a). Furthermore, alcohol-stimulated microglial cells also exhibit much increased synthesis and release of AGE-albumin and induce neuronal cell death (Byun et al., 2014).
5. Development of therapeutics against AGEs
Developmental efforts have resulted in many agents that reduce the damage induced by AGEs. These agents can be summarized as AGEs inhibitors and breakers, angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, antioxidants, natural substances, and anti-inflammatory molecules (Table 2).
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5.1 AGEs inhibitors & breakers AGEs inhibitors that prevent AGEs formation and AGEs cross-link breakers were identified
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as initial efforts. Aminoguanidine was the first AGEs inhibitor found to inhibit the formation
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of AGEs, and was also reported to effectively reduce the pathologic effects of the nephropathy and vascular complications associated with AGEs in diabetes (Brownlee et al.,
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1986; Freedman et al., 1999, Bolton et al., 2004). Several AGEs cross-link breakers have also been reported to effectively reduce AGEs products and proposed as possible therapeutics for the treatment of diabetic vascular complications. Alagebrium and related compounds
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including ALT-711, ALT-462, ALT-486, and ALT-946 apparently break some existing AGEs cross-links (Krautwald et al., 2011). ALT 711 was initially reported to effectively reduce the
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severity of AGE-induced pathological lesions (Vasan et al., 2001). Another AGEs-breaker, TRC4186, was reported to inhibit AGEs formation or break AGEs cross-links and to
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ameliorate diabetes-related cardiomyopathy and nephropathy (Joshi et al., 2009).
5.2 Angiotensin II receptor antagonist and angiotensin converting enzyme
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inhibitor
Telmisartan, an anti-hypertension drug and angiotensin II receptor blocker, was found to decrease AGEs formation. For example, a clinical study demonstrated telmisartan decreased
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RAGE expression by activating PPAR- in liver (Yoshida et al., 2006). In addition, pyridoxamine has been reported as preventing the Amadori reaction leading to AGEs formation (Thomas et al., 2005; Adrover et al., 2008).
5.3 Antioxidants Antioxidants have been developed to inhibit AGEs. Statins, which have antioxidant activity, are commonly used to lower blood cholesterol levels. The antioxidant effect of statins was found to inhibit reactive protein C release effectively from toxic AGEs, and thus, to prevent diabetes-associated vascular complications (Ajith et al., 2006; 2008; Takeuchi et al., 2010). Atorvastatin was introduced as means of decreasing serum AGEs levels in patients with type 2 diabetes in a soluble RAGE (sRAGE) and a splice variant of sRAGE dependent manner (Jinnouchi et al., 2006; Tam et al., 2010). Other study supported the notion that
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atorvastatin restored reduced glutathione levels, inhibited RAGE up-regulation, and downregulated the expression of RAGE and MCP-1 (Feng et al., 2011). Recently, a RAGE
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antagonist from the part of human serum albumin was found to reduce the increased NF-κB
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signaling by anti-inflammatory mechanism (Maltais et al., 2016). Ascorbic acid, alpha-lipoic acid, carnosine, and quercetin have been shown to inhibit AGEs effectively (Bierhaus et al.,
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1997; Abdul & Butterfield, 2007; Guiotto et al., 2005; Zafar, 2012; Ashraf et al., 2015). Recently the glucagon-like peptide-1 receptor agonist exendin, and NF-κB inhibitor-pyrrolidine dithiocarbamate were also showed to provide strong in vitro protection against AGEs-
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induced neuronal apoptosis by reducing the overexpression of RAGE (Chen et al., 2016).
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5.4 Natural substances
Studies have shown some natural substances, such as resveratrol and curcumin, can prevent
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AGEs-induced pathology (Mizutani et al., 2000). Resveratrol inhibited the AGE-induced
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proliferation of collagen in smooth muscle cells of blood vessels (Mizutani et al., 2000), and curcumin blocked the effect of AGEs on the RAGE expression (Tang, 2014). Recently, new
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prenylflavonoids were reported to inhibit the formations of N(6)-carboxymethyllysine (CML) and N(omega)-carboxymethylarginine (CMA) in the methanol extract of the aerial portions of Epimedii Herba (Nakashima et al., 2016). Similarly, p-cymene, a monoterpene was
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demonstrated to act as AGEs breakers for AGEs cross-linking (Joglekar et al., 2014; Lee et al., 2014). Recently, sulphoraphene was demonstrated to inhibit inflammation in AGEs-exposed human umbilical vein endothelial cells (HUVECs) and AGEs-infused rat aorta partly by suppressing RAGE expression (Matsui et al., 2016). Vitamin D also reported as reducing the risk of CVDs. AGEs, such as CML, have been implicated in diabetic vascular complications via oxidative stress-mediated pathways (Salum et al., 2013). Gymnema also reported to contribute to the anti-hyperglycemic effects (Sugihara et al., 2000), and metformin has been reported to restore glycated high-density lipoprotein (HDL)-mediated cholesterol efflux (Matsuki et al., 2009). Epigallocatechin gallate (EGCG), a major component of green tea polyphenols, showed protective effects against AGEs-induced damage in neuron cells (Lee & Lee, 2007), and S-allyl cysteine from aged garlic has been reported to act as a potent
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antioxidant and inhibit AGEs protein formation (Ahmad & Ahmad, 2006). Ramipril has also
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been reported to be an efficient AGEs inhibitor as well (Gosse & Schumacher, 2014).
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5.5 Anti-inflammatory molecules and AGEs inhibitors that act on activated
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macrophages
Anti-inflammatory molecules have also been found to reduce the toxic effects of AGEs. In particular, LR-90 had been shown to inhibit the NF-κB activation, which stimulates the gene expressions of proinflammatory molecules in human monocytes (Figarola et al, 2007).
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Bisphosphonates were found to inhibit toxic AGEs-mediated inflammation and finally stopped ROS formation during the pathogeneses of the vascular complications of diabetes
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(Takeuchi et al., 2010). Similarly, another nitrogen-containing bisphosphonate, minodronate, inhibited signaling pathways initiated by the interaction between AGEs and RAGE in
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diabetic retinopathy (Yamagishi et al., 2006). It appears that inhibitors of AGEs with anti-
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inflammatory effects can deactivate macrophages and reduce tissue damage as well. Because most known therapeutic reagents used to treat diabetes target AGEs in blood, AGEs
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inhibition in activated macrophages located in tissues has been investigated as a novel targeting strategy. The sRAGE-based masking of secreted AGEs has shown strong potent therapeutic effects in several diseases, such as AD, PD, alcoholic brain damage, and AMI
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(Byun et al., 2012a; 2014; Bayarsaikhan et al., 2016) (Fig. 5). Since sRAGE is the extracellular part of RAGE, it can bind to AGEs, and thus, prevent their adverse effects. Targeting AGEs in activated macrophage probably could be one of the most ideal strategies for AGEs related diseases.
6. Conclusion and future perspectives
The role played by the AGEs-RAGE interaction in the aggravation of the chronic complications of diabetes, CVDs, and degenerative diseases has been well established. The interaction between AGEs and RAGE on the plasma membrane triggers the downstream signaling of inflammation, oxidative stress, and apoptosis in many cells, including neurons, endothelial cells, lung cells and muscle cells. Therapeutic agent development has focused
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mainly on suppressing AGEs or RAGE formation or preventing the AGEs-RAGE interaction. Although agents have been devised to prevent AGEs formation and activity, most are under
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in the early phase of clinical studies. Similarly, studies on natural substances like resveratrol
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and curcumin have been described to inhibit RAGE-associated vascular damage and the long-term complications of diabetes. Furthermore, sRAGE and its variants can inhibit the
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interaction between AGEs and RAGE effectively and have also been suggested to be promising therapeutic agents.
Recently, it was found that activated macrophages are one of primary contributors to AGE-
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albumin accumulation in tissues, and suggested AGE-albumin is a potentially useful therapeutic and diagnostic biomarker with high sensitivity and resolution. In addition,
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labeling and visualizing accumulated AGE-albumin with proper antibodies may provide a near ideal theragnostic means to combat AGEs/RAGE associated diseases. In conclusion, more studies are required to determine how to prevent, remove, and estimate
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the AGEs/RAGE interaction in relation to macrophage activation and to elucidate its
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pathophysiologic mechanism in many intractable diseases.
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Conflict of interest statement
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The authors declare that there are no conflicts of interest.
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Acknowledgments
This work was supported by the Korean Health Technology R&D Project through the Korean Health Industry Development Institute (KHIDI), funded by the Ministry of Health &
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Welfare, Republic of Korea (Lee, B., grant no. HI13C2098), and by the National Research
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Foundation of Korea (Byun, K., grant no. 2015R1A2A2A01005212).
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Legends for Figures
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Fig. 1. Association of advanced glycation end products (AGEs) and human diseases. AGEs are related to disease incidence of several organs through common mechanism of oxidative stress, neovascularization, inflammation or cross linking with extracellular matrix (ECM).
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Fig. 2. AGEs from activated macrophage and its receptor mediated tissue injury via mitochondrial dysfunction. AGE is one of major five protein modification induced by ROS/RNS after exposure to alcohol, high fat diet, tobacco, drugs or gene alterations. AGEs induce RAGE increase and mitochondrial dysfunction leading to tissue injury.
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Fig. 3. Cell specific ligands for Receptor for AGEs (RAGE) and their high-lighted signaling pathways in relevant diseases. AD; Alzheimer’s disease, PD; Parkinson’s disease, Alc; Alcoholic brain damage, AMI; Acute myocardial infarction, LC; Liver cirrhosis, IPF; Idiopathic pulmonary fibrosis, DN; diabetic nephropathy, OA; osteoarthritis, F; fibrosis, I; inflammation, O; oxidative stress, A; autophagy, D; degeneration, Cd; cell death
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Fig. 4. Activators of macrophages and secreted proteins from activated macrophages. RAGE ligands also induce activation of macrophages and they are secreted from activated macrophages. AGEs; advanced glycation end products, HMGB1; high-mobility group protein B1, Mac-1; macrophage-1 antigen, LPS; lipopolysaccharide, Aβ; amyloid beta, IL-10; interleukin-10, NO; nitric oxide, ROS; reactive oxygen species
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Fig. 5. A proposed model of AGE albumin from activated macrophage and its relevancy to cell death in various tissues.
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Table 1. RAGE ligands that activate macrophages under inflammatory conditions and in degenerative diseases Reference
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Acute myocardial injury Osteoarthritis Alzheimer’s disease Spinal cord injury Hypertension Liver cirrhosis Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis Acute lung injury
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Spinal cord injury Stroke
S100A8/9 Aβ LPS
Crews & Vetreno, 2014 Crews & Vetreno, 2016 Kikuchi et al., 2011 Liesz et al., 2015 Xiong et al., 2016 Herzog et al., 2014 van Lent et al., 2012 Fang et al., 2010 Xie et al., 2004 Hernanz et al., 2004 Jirillo et al., 2002 Miles et al., 1999 Freeburn et al., 2005 Zhu et al., 2013
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Alcoholic brain damage
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HMGB1
Disease
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Cytokine
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Table 2. Therapeutic agent for AGEs and RAGE related pathology in disease Name
Reference
AGEs inhibitor
Aminoguanidine
Brownlee et al., 1986 Freedman et al., 1999 Bolton et al., 2004
AGEs cross link breaker
Alagebrium and related compounds (ALT-711, ALT-462, ALT-486, ALT-
Vasan et al., 2001 Joshi et al., 2009
Telmisartan
Antioxidant
Statins
Yoshida et al., 2006
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Angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor
Pyridoxamine
Thomas et al., 2005 Adrover et al., 2008
Resveratrol Curcumin
Mizutani et al., 2000 Tang, 2014
Prenylflavonoids
Nakashima et al., 2016
p-Cymene
Joglekar et al., 2014
Chebulic acid of Terminalia chebula, sulphoraphene Vitamin D Gymnema Metformin Epigallocatechin Gallate S-allylcysteine Ramipril
Lee et al., 2014 Matsui et al., 2016 Salum et al., 2013 Sugihara et al., 2000 Matsuki et al., 2009 Lee & Lee, 2007 Ahmad & Ahmad, 2006 Gosse & Schumacher, 2014.
LR-90
Figarola, et al, 2007
Bisphosphonates
Takeuchi et al., 2010
Minodronate
Yamagishi et al., 2006
MA
RAGE antagonist Ascorbic acid Alpha-lipoic acid
NU
Exendin Pyrrolidine dithiocarbamate
Ajith et al., 2006 Ajith et al., 2008 Takeuchi et al., 2010 Jinnouchi et al., 2006 Tam et al., 2010 Feng et al., 2011 Maltais et al., 2016 Zafar, 2012 Bierhaus et al., 1997 Abdul & Butterfield, 2007 Abdul & Butterfield, 2007 Ashraf et al., 2015 Dhumale et al., 2015 Chen et al., 2016 Chen et al., 2016
Atorvastatin
TE
D
Carnosine Quercetin
AC
CE P
Natural substance
Anti-inflammatory molecules
Krautwald et al., 2011
IP
TRC4186
T
Category
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
AC
CE P
TE
Figure 1
AC
Figure 2
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
AC
CE P
TE
D
Figure 3
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
AC
CE P
TE
D
Figure 4
AC
Figure 5
CE P
TE
D
MA
NU
SC R
IP
T
ACCEPTED MANUSCRIPT
