Receptor for Advanced Glycation End Products (RAGE): A Pivotal Hub in Immune Diseases

Abstract

As a critical molecule in the onset and sustainment of inflammatory response, the receptor for advanced glycation end products (RAGE) has a variety of ligands, such as advanced glycation end products (AGEs), S100/calcium granule protein, and high-mobility group protein 1 (HMGB1). Recently, an increasing number studies have shown that RAGE ligand binding can initiate the intracellular signal cascade, affect intracellular signal transduction, stimulate the release of cytokines, and play a vital role in the occurrence and development of immune-related diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Alzheimer's disease. In addition, other RAGE signaling pathways can play crucial roles in life activities, such as inflammation, apoptosis, autophagy, and endoplasmic reticulum stress. Therefore, the strategy of targeted intervention in the RAGE signaling pathway may have significant therapeutic potential, attracting increasing attention. In this paper, through the systematic induction and analysis of RAGE-related signaling pathways and their regulatory mechanisms in immune-related diseases, we provide theoretical clues for the follow-up targeted intervention of RAGE-mediated diseases.

Keywords: advanced glycation end-product receptor; high-mobility group protein 1; immune; nuclear factor kappa-B.

Figure 1

RAGE structural organization. The extracellular domain comprises three domains: V, C1, and C2. One transmembrane receptor passes through the plasma membrane bilayer, followed by an intracellular cytoplasmic tail. The extracellular region without a transmembrane receptor and a cytoplasmic tail is called soluble RAGE (sRAGE).

Figure 2

RAGE regulates the MAPK/NF-κB signaling pathway. After binding to the ligand, RAGE phosphorylates its downstream MAPK and activates NF-κB protein. NF-κB enters the nucleus to promote the transcriptional expression of inflammatory factors. Abbreviations: AGEs: advanced glycation end products; HMGB1: high-mobility group protein 1; RAGE: receptor for advanced glycation end products; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-B; TNF-α: tumor necrosis factor α; IL-1β: interleukin-1β.

Figure 3

The mechanism of action of RAGE–ligand binding in RA. The binding of RAGE with the ligand activates the MAPK/NF-κB signaling pathway and induces the production of inflammatory factors. sRAGE can block the ligand–RAGE interaction on the cell surface, reducing the entry of inflammatory cells into the joint cavity. Abbreviations: RAGE: receptor for advanced glycation end products; sRAGE: soluble receptor for advanced glycation end products; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-B; IκB: inhibitor of NF-κB; TNF-α: tumor necrosis factor α; IL-1: interleukin-1; IL-17: interleukin-17.

Figure 4

RAGE-related signaling pathways in Alzheimer’s disease. After APP is converted to Aβ, on the one hand, it combines with RAGE to activate the downstream MAPK/NF-κB pathway to release inflammatory factors and damages nerve cells. On the other hand, Aβ binds to RAGE on the surface of BBB cells, causing ERS, altering the permeability of the BBB, increasing the concentration of Aβ in the central nervous system, and aggravating AD-related symptoms. Abbreviations: APP: amyloid prebiotic protein; Aβ: amyloid β-protein; RAGE: receptor for advanced glycation end products; GSK-3β: glycogen synthase kinase 3β; PERK: protein kinase R-like endoplasmic reticulum kinase; eIF2α: eukaryotic translation initiation factor 2α; NOX: nitrogen oxide; NF-κB: nuclear factor kappa-B; IκB: inhibitor of NF-κB; TNF-α: tumor necrosis factor α; IL-1β: interleukin-1β; IL-6: interleukin-6; M-CSF: macrophage colony-stimulating factor.

Figure 5

Nrf2 regulates the related pathways of RAGE expression. After being stimulated by oxidative stress and other stimuli, Nrf2 breaks away from keap1 and deactivates Glo1, which can reduce the production of AGEs, thereby regulating the level of RAGE expression. Similarly, after Nrf2 is activated, it can activate its downstream HO-1 to exert its antioxidant effect, inhibit the oxidation of HMGB1, and regulate the expression of RAGE. Abbreviations: ROS: reactive oxygen species; Nrf2: nuclear factor E2-related factor 2; Keap1: Kelch-like epichlorohydrin-related protein-1; Glo1: glyoxylate 1; HO-1: heme oxygenase 1; MGO: methyl glyoxal; AGEs: advanced glycation end products; HMGB1: high-mobility group protein 1.