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RAGE (receptor)

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(Redirected from AGER)

"AGER" redirects here. For other uses, see Ager (disambiguation).
AGER
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesAGER, Ager, RAGE, SCARJ1, advanced glycosylation end product-specific receptor, advanced glycosylation end-product specific receptor, sRAGE
External IDsOMIM: 600214; MGI: 893592; HomoloGene: 883; GeneCards: AGER; OMA:AGER - orthologs
Orthologs
SpeciesHumanMouse
Entrez

177

11596

Ensembl

ENSMUSG00000015452

UniProt

Q15109

Q62151

RefSeq (mRNA)

NM_001271422
NM_001271423
NM_001271424
NM_007425

RefSeq (protein)

NP_001258351
NP_001258352
NP_001258353
NP_031451

Location (UCSC)Chr 6: 32.18 – 32.18 MbChr 17: 34.82 – 34.82 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Schematic of the relation between an immunoglobulin and RAGE
Schematic of the RAGE gene and its products

RAGE (receptor for advanced glycation endproducts), also called AGER, is a 35 kilodalton transmembrane receptor[5] of the immunoglobulin super family which was first characterized in 1992 by Neeper et al.[6] Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.

The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation.[7][8] Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.

Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.

Gene and polymorphisms

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The RAGE gene lies within the major histocompatibility complex (MHC class III region) on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pairs (bp) including the promoter region, which partly overlaps with the PBX2 gene.[9] About 30 polymorphisms are known most of which are single-nucleotide polymorphisms.[10]

RNA and alternative splicing

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The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively spliced. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.

Structure

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RAGE exists in the body in two forms: a membrane-bound form known as mRAGE, and a soluble form, known as sRAGE. mRAGE has three domains, and sRAGE has only the extracellular domain. sRAGE is either the product of alternative splicing or the product of proteolytic cleavage of mRAGE.[11]

The full receptor consists of the following domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands, and two constant domains.[citation needed]

Membrane-bound (mRAGE)

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The membrane-bound form of RAGE, commonly known as mRAGE, is a full-length receptor comprising several important structural domains:

  1. Extracellular Domain: The extracellular domain is composed of multiple immunoglobulin-like subdomains, including the variable (V) domain and two constant domains (C1 and C2). The V domain serves as the principal binding site for a wide range of ligands, such as advanced glycation end-products (AGEs), S100 proteins, and high mobility group box 1 (HMGB1). This ligand-binding feature is essential for triggering downstream signaling cascades that lead to inflammatory responses.[12]
  2. Transmembrane Domain: The transmembrane domain helps anchor RAGE in the cellular membrane, ensuring that the receptor remains available to interact with extracellular ligands and transmit signals into the cell.[12]
  3. Cytoplasmic Domain: The cytoplasmic domain, also referred to as the cytosolic domain, is integral for intracellular signal transduction. When ligands bind to the extracellular domain, this segment interacts with intracellular signaling proteins, initiating processes such as the activation of NF-κB, a key inflammatory pathway. It has been observed that the absence of the cytoplasmic domain impairs the receptor's ability to transmit signals effectively, which underlines its importance in RAGE-mediated signaling.[12]

Soluble (sRAGE)

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The soluble form of RAGE (sRAGE) only includes the extracellular domain and lacks both the transmembrane and cytoplasmic domains. sRAGE can be generated through two primary mechanisms:

  1. Alternative Splicing: In this mechanism, alternative splicing of the RAGE gene produces a variant that lacks the membrane-anchoring and cytoplasmic segments, creating a soluble form of the receptor[13]
  2. Proteolytic Cleavage: Alternatively, sRAGE can be produced by proteolytic cleavage of the membrane-bound receptor. This involves enzymes, such as matrix metalloproteinases (MMPs) and ADAM10, cleaving the extracellular portion of mRAGE, which is then released into the circulatio.[13]

Function

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  • Membrane-Bound RAGE (mRAGE): mRAGE acts as a cellular receptor capable of activating inflammatory and oxidative stress pathways in response to ligand binding. The receptor's structure, which includes the ligand-binding domain, transmembrane segment, and cytoplasmic tail, is critical for these functions. The wide variety of ligands that interact with mRAGE contributes to its involvement in multiple pathological states, such as diabetes, neurodegeneration, and cardiovascular diseases.[13]
  • Soluble RAGE (sRAGE): On the other hand, sRAGE functions as a decoy receptor. It circulates in the bloodstream and binds RAGE ligands, thereby preventing them from activating mRAGE on the cell surface. By neutralizing these ligands, sRAGE reduces RAGE-mediated cellular activation and inflammation. Elevated levels of sRAGE are considered to have a protective effect in inflammatory diseases by limiting the activity of harmful ligands.[13]

The balance between mRAGE and sRAGE levels is thought to influence disease outcomes. An excess of mRAGE is often associated with inflammation and disease progression, whereas higher concentrations of sRAGE may be beneficial in mitigating inflammatory responses.

Therapeutic insights

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The distinct structure of RAGE makes it a potential target for therapeutic intervention, particularly in conditions involving chronic inflammation. Inhibitors that prevent ligand binding to the V domain have been studied to reduce downstream inflammatory signaling. Targeting the cytoplasmic domain to disrupt intracellular signal transduction is another approach being explored. Additionally, increasing the levels of sRAGE could serve as an effective strategy to neutralize pro-inflammatory ligands and limit their interaction with mRAGE, offering potential benefits in treating inflammatory conditions.[13]

Ligands

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RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Ligands which have so far been found to bind RAGE are:

Binding mechanism

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The receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily, originally identified due to its ability to bind advanced glycation end products (AGEs). AGEs accumulate in various chronic conditions such as diabetes and renal failure. However, RAGE also binds other ligands, notably proteins of the S100/calgranulin family, such as EN-RAGE and S100B, which play significant roles in inflammatory processes.[19]

RAGE ligands interact with the receptor through its extracellular domain, triggering a cascade of intracellular signaling pathways. These pathways lead to the activation of key transcription factors like nuclear factor kappa B (NF-κB), which is central to the expression of proinflammatory cytokines, adhesion molecules (such as VCAM-1 and ICAM-1), and other mediators of inflammation.[19] Upon binding ligands like EN-RAGE or S100B, RAGE stimulates various inflammatory responses, including endothelial cell activation, mononuclear cell migration, and the production of cytokines such as TNF-α and IL-1β.[19]

These interactions between RAGE and its ligands contribute to chronic inflammatory conditions, including atherosclerosis, Alzheimer's disease, and diabetic complications. Inhibiting the RAGE-ligand interaction—through the use of soluble RAGE (sRAGE) or specific antibodies—can suppress these inflammatory responses, offering potential therapeutic strategies.[19]

Receptors

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Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in the removal of AGE rather than in signal transduction as is the case for RAGE. Other AGE receptors are:

  • SR-A (Macrophage scavenger receptor Type I and II) : The macrophage scavenger receptor types I and II help clear modified proteins, including AGEs. This process is essential for macrophage-mediated removal of potentially harmful AGEs from circulation, reducing oxidative stress and inflammation.
  • OST-48 (Oligosaccharyl transferase-4) (AGE-R1): Also known as AGE-R1, OST-48 has been implicated in AGE detoxification, helping to prevent AGE accumulation, particularly in diabetic complications. AGE-R1 expression has been correlated with decreased AGE-induced cellular toxicity, making it a potential protective factor in AGE-related pathologies.
  • 80 K-H phosphoprotein (Proteinkinase C substrate) (AGE-R2):The 80 K-H phosphoprotein, also known as protein kinase C substrate, is thought to be involved in the signaling response to AGE exposure. AGE-R2 helps regulate intracellular pathways that may contribute to the cell's response to oxidative stress.
  • Galectin-3 (AGE-R3):Galectin-3 is a lectin that binds AGEs and facilitates their removal from the extracellular space. It plays a role in modulating processes such as apoptosis, cell growth, and immune response, which helps in reducing AGE-induced tissue damage.
  • LOX-1 (Lectin-like oxidized low density lipoprotein receptor-1):LOX-1 is known for its role in binding oxidized lipoproteins but also binds AGEs. It is involved in endothelial dysfunction and atherosclerotic plaque formation, suggesting that AGE binding by LOX-1 can exacerbate vascular complications, particularly in metabolic disorders.
  • CD36:The CD36 receptor is another important receptor for AGEs, primarily involved in facilitating the uptake and clearance of AGE-modified proteins. It plays a role in inflammation and oxidative stress, with expression on cells like macrophages, endothelial cells, and adipocytes. CD36 involvement in AGE recognition contributes to lipid metabolism and immune response regulation.
  • SR-BI (Scavenger Receptor Class B Type I):SR-BI is primarily known for mediating cholesterol transport, but it has also been implicated in the recognition and binding of AGEs. It plays a role in lipid metabolism and contributes to the cellular uptake of AGE-modified proteins, thus helping in AGE clearance and reducing potential cellular stress.
  • LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1):LRP1 is involved in the endocytosis of various ligands, including AGEs. LRP1 functions by promoting cellular uptake and degradation of AGE-modified proteins, helping to protect against oxidative damage and inflammation that arise from AGE accumulation. LRP1 is found in a variety of tissues, including the liver and vascular smooth muscle cells.
  • MSR1 (Macrophage Scavenger Receptor 1):The macrophage scavenger receptor 1 (MSR1) is an important receptor in the immune system, involved in the phagocytic uptake of AGEs. It helps macrophages recognize and degrade modified proteins, contributing to the reduction of inflammation and cellular stress in the tissues exposed to AGEs.
  • FEEL-1/CLEC14A (Facultative Endothelial Lectin-1): FEEL-1, also known as CLEC14A, is a member of the C-type lectin receptor family. It has been found to interact with AGEs and participate in their clearance. This receptor is primarily expressed on endothelial cells and plays a role in maintaining vascular health by reducing the burden of AGE-modified proteins.
  • SR-BII (Scavenger Receptor Class B Type II):SR-BII is similar to SR-BI but has distinct functions. It binds AGEs and has been implicated in mediating the uptake of modified proteins. SR-BII is involved in lipid transfer processes and, like SR-BI, may contribute to mitigating AGE-induced cellular stress.
  • DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin): DC-SIGN is a receptor expressed on dendritic cells that plays a key role in pathogen recognition and immune response. Emerging research suggests that DC-SIGN can bind AGEs and mediate their clearance, reducing AGE-induced immune activation.

Clinical significance

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RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding, upon which RAGE signals activation of nuclear factor kappa B (NF-κB). NF-κB controls several genes involved in inflammation. RAGE itself is upregulated by NF-κB. Given a condition in which there is a large amount of a RAGE ligand present (e.g. AGE in diabetes or amyloid-β-protein in Alzheimer's disease) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature, resulting in organ damage or even organ failure.[20] However, whilst RAGE is up-regulated in inflammatory conditions, it is down-regulated in lung cancer and pulmonary fibrosis.[11]

Diseases that have been linked to RAGE include:[citation needed]

Lungs

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RAGE is expressed at its highest levels in the lung compared to other tissues, especially in alveolar type I cells. In cases of idiopathic pulmonary fibrosis (IPF), RAGE expression is lost, indicating that its regulation and expression in the pulmonary system differ from that in the vascular system. Studies show that blocking or knocking down RAGE impairs cell adhesion and increases cell proliferation and migration.[26]

Diabetes

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RAGE plays a pivotal role in the pathogenesis of diabetes. RAGE, a multi-ligand receptor from the immunoglobulin superfamily, primarily binds to Advanced glycation end-products (AGEs) formed through the non-enzymatic glycation of proteins and lipids. In diabetes, hyperglycemia accelerates AGE formation, fostering a pro-inflammatory and pro-oxidative environment that worsens vascular damage and immune cell dysfunction.[27][28]

In both type 1 and type 2 diabetes, RAGE significantly contributes to microvascular and macrovascular complications. It is highly expressed in diabetic blood vessels, cardiomyocytes, podocytes, and immune cells, where it co-localizes with ligands such as AGEs, S100 proteins, and high-mobility group box 1 (HMGB1). This co-localization leads to chronic cellular stress and inflammation, which differs from the transient inflammatory responses associated with acute infections.[27]

RAGE activation contributes to complications such as diabetic nephropathy and retinopathy. Studies in diabetic mouse models suggest that blocking RAGE with soluble receptor forms (sRAGE) can mitigate these conditions by reducing mesangial sclerosis, basement membrane thickening, and endothelial damage.[27] Additionally, RAGE’s interaction with AGEs and S100 proteins accelerates atherosclerosis in diabetes, marked by increased lesion complexity, macrophage accumulation, and vascular inflammation.

Cardiovascular disease

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Beyond diabetes, RAGE is crucial in cardiovascular disease pathogenesis, particularly atherosclerosis. Although RAGE is present in atherosclerotic plaques in both diabetic and non-diabetic patients, its expression is heightened in diabetic individuals. RAGE activation in smooth muscle cells, endothelial cells, and macrophages promotes atherosclerotic lesion development through mechanisms involving oxidative stress, inflammatory signaling, and immune cell recruitment.[27]

RAGE-mediated signaling exacerbates vascular inflammation, endothelial dysfunction, and plaque instability. Animal studies demonstrate that blocking RAGE in diabetic models can reduce lesion formation and improve vascular function, even without affecting blood glucose levels.[27][28]

As a drug target

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Given its prominent role in both diabetes and CVD, RAGE is a promising therapeutic target. Preclinical and clinical studies are exploring RAGE antagonism to treat these conditions. Blocking RAGE signaling, either through pharmacological inhibitors or soluble decoy receptors like sRAGE, has shown potential in reducing vascular complications in diabetic patients. These strategies may offer new ways to manage the chronic inflammation and oxidative stress that drive both diabetic complications and cardiovascular disease progression[28]

RAGE's role in diabetes and cardiovascular disease highlights the importance of its signaling pathway in mediating chronic inflammation and vascular damage. Targeting RAGE could offer a promising approach to mitigating the burden of these diseases, particularly in patients with diabetes, where current therapies may fall short in preventing cardiovascular complications.

Inhibitors

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A number of small molecule RAGE inhibitors or antagonists have been reported.[29][30][31][32]

Azeliragon
vTv Therapeutics (formerly TransTech Pharma) sponsored a Phase 3 clinical trial of their RAGE inhibitor Azeliragon (TTP488) for mild Alzheimer's disease.[33][34] These trials were halted in 2018.[35]
RAP (Receptor Antagonist Peptide)
RAP is a peptide-based inhibitor that functions by directly competing with RAGE ligands for binding, thereby inhibiting RAGE-mediated signaling. It has shown potential in reducing vascular inflammation and preventing atherosclerosis in experimental models. RAP's ability to block the RAGE-ligand interaction has made it a candidate for cardiovascular disease therapies, particularly those involving chronic inflammation.
FPS-ZM1
FPS-ZM1 is a well-known small molecule inhibitor of RAGE, designed to cross the blood-brain barrier and effectively block RAGE signaling in the central nervous system. Studies have demonstrated that FPS-ZM1 significantly reduces neuroinflammation and β-amyloid accumulation in mouse models of Alzheimer's disease. By inhibiting RAGE, FPS-ZM1 aims to reduce oxidative stress and inflammation associated with neurodegenerative processes, showing promise in preclinical studies for treating Alzheimer's disease and other neuroinflammatory conditions.[36]

Research

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Extracellular vesicle cross-talk

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Recent studies have highlighted the involvement of RAGE (Receptor for Advanced Glycation End-products) in mediating the intercellular communication through extracellular vesicles (EVs), particularly during inflammatory responses. RAGE, known for its interaction with various ligands including advanced glycation end-products (AGEs), plays a key role in the biogenesis and secretion of EVs from stressed or damaged cells. Extracellular vesicles, such as exosomes, are small lipid-bound vesicles that facilitate cell-to-cell communication by transferring molecular cargo including proteins, lipids, and RNAs between cells. Recent evidence suggests that RAGE-associated vesicular pathways contribute to the exacerbation of inflammation by enabling pro-inflammatory signaling between cells.[5][8]

Specifically, a study from 2023 demonstrated that β-cells exposed to cytokine-induced stress release EVs enriched with RAGE ligands, which were found to further activate RAGE signaling pathways in neighboring cells, promoting inflammatory responses and impairing insulin secretion. These EV-mediated effects were shown to propagate inflammation across multiple cell types, indicating that RAGE-associated vesicles may play a pivotal role in amplifying the immune response in metabolic disorders like diabetes.[14] Another study from 2024 reported that EVs containing RAGE ligands could be detected in the bloodstream of patients with early-stage diabetes, suggesting the potential utility of these vesicles as biomarkers for early diagnosis of inflammatory diseases.[15]

Furthermore, these findings emphasize the dual role of RAGE in both EV biogenesis and as a mediator of inflammation through vesicular cross-talk, which has implications for targeting RAGE-EV interactions in therapeutic strategies aimed at mitigating inflammatory diseases.

Role in aging

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The relationship between RAGE signaling and aging has been a growing focus of research, particularly in the context of cellular senescence and inflammaging—chronic, low-grade inflammation associated with aging. RAGE has been implicated in promoting cellular senescence, a permanent state of cell-cycle arrest, which contributes to the accumulation of dysfunctional cells that secrete pro-inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP).

A study conducted in 2022 demonstrated that the activation of RAGE by AGEs in aged tissues leads to the accumulation of senescent cells, thereby exacerbating tissue inflammation and contributing to age-related diseases. This study also noted that the upregulation of RAGE in aged cells increased the secretion of SASP factors, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), both of which are key mediators of inflammaging.[16]

Another recent investigation from 2023 found that mice deficient in RAGE exhibited reduced markers of senescence and systemic inflammation compared to age-matched controls, suggesting that targeting RAGE signaling may be a promising approach to mitigate the adverse effects of aging and extend healthspan. These findings highlight the role of RAGE as a crucial regulator of the inflammatory milieu associated with aging, providing potential avenues for therapeutic interventions aimed at reducing age-related inflammatory diseases.[17]

References

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  33. ^ "Azeliragon". vTv Therapeutics. Retrieved 23 July 2015.
  34. ^ Clinical trial number NCT02080364 for "Evaluation of the Efficacy and Safety of Azeliragon (TTP488) in Patients With Mild Alzheimer's Disease (STEADFAST)" at ClinicalTrials.gov
  35. ^ vTv Halts Trials of Alzheimer's Candidate Azeliragon after Phase III Failure Apr 2018
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Further reading

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