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.

The RAGE gene lies within the major histocompatibility complex (MHC class III region) on chromosome 6 and comprises 11 exons interlaced by 10 introns.

sRAGE can be produced by two different mechanisms: either through alternative splicing of the RAGE gene, leading to a truncated form that lacks the transmembrane and cytosolic regions, or through proteolytic cleavage of mRAGE by specific enzymes such as ADAM10 or matrix metalloproteinases (MMPs).

[14][15] The full RAGE receptor plays an important role in cellular communication, interacting with a diverse set of ligands, including advanced glycation end products (AGEs), amyloid-β peptides, and S100 proteins.

These interactions activate multiple downstream signaling pathways that contribute to cellular stress responses and are linked to the development of various inflammatory and metabolic conditions.

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.

This receptor also plays a role in modulating inflammatory signaling pathways, thereby contributing to the regulation of tissue homeostasis and preventing chronic inflammation caused by AGE accumulation.

AGE-R2 plays a role in regulating pathways that help cells adapt to oxidative stress by modulating protein kinase C (PKC) activity.

Upon binding AGEs, Galectin-3 activates downstream signaling pathways, including those involving mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB), which are crucial for inflammatory regulation.

CD36 is an important scavenger receptor expressed on macrophages, endothelial cells, and adipocytes, and it plays a major role in the recognition and uptake of AGE-modified proteins.

The receptor also interacts with signaling pathways that regulate inflammation, making it an important factor in protecting against AGE-induced vascular and metabolic complications.

[33] The interaction of FEEL-1 with AGEs is thought to reduce endothelial cell activation and inflammation, contributing to the protection of blood vessels from AGE-induced damage and maintaining vascular integrity.

[34] By participating in lipid metabolism and AGE clearance, SR-BII contributes to mitigating oxidative damage and supporting cellular homeostasis.

Recent research suggests that DC-SIGN can also bind AGEs and mediate their clearance, which helps reduce AGE-induced immune activation.

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.

In diabetes, hyperglycemia accelerates AGE formation, fostering a pro-inflammatory and pro-oxidative environment that worsens vascular damage and immune cell dysfunction.

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).

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.

[44] Additionally, RAGE’s interaction with AGEs and S100 proteins accelerates atherosclerosis in diabetes, marked by increased lesion complexity, macrophage accumulation, and vascular inflammation.

Animal studies demonstrate that blocking RAGE in diabetic models can reduce lesion formation and improve vascular function, even without affecting blood glucose levels.

Blocking RAGE signaling, either through pharmacological inhibitors or soluble decoy receptors like sRAGE, has shown potential in reducing vascular complications in diabetic patients.

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.

[46][47][48][49] 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.

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.

[19] 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.

[20] 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.

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).

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.