The RAGE Pathway in Skin Pathology Development: A Comprehensive Review of Its Role and Therapeutic Potential

Abstract

The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, is expressed in various cell types and mediates cellular responses to a wide range of ligands. The activation of RAGE triggers complex signaling pathways that drive inflammatory, oxidative, and proliferative responses, which are increasingly implicated in the pathogenesis of skin diseases. Despite its well-established roles in conditions such as diabetes, cancer, and chronic inflammation, the contribution of RAGE to skin pathologies remains underexplored. This review synthesizes current findings on RAGE's involvement in the pathophysiology of skin diseases, including conditions such as psoriasis, atopic dermatitis, and lichen planus, focusing on its roles in inflammatory signaling, tissue remodeling, and skin cancer progression. Additionally, it examines RAGE-modulating treatments investigated in dermatological contexts, highlighting their potential as therapeutic options. Given RAGE's significance in a variety of skin conditions, further research into its mediated pathways may uncover new opportunities for targeted interventions in skin-specific RAGE signaling.

Keywords: RAGE; fibrosis; inflammation; skin diseases; skin neoplasms.

Figure 1

The cell membrane receptor for advanced glycation end-products (RAGE) consists of a VC1 domain, a C2 domain, and both transmembrane and intracellular regions. RAGE binds a range of endogenous danger-associated molecular patterns (DAMPs) and exogenous pathogen-associated molecular patterns (PAMPs) through its positively charged VC1 domain. Key ligands include advanced glycation end-products (AGEs), advanced oxidation protein products (AOPPs), high-mobility group box 1 (HMGB1), S100 family proteins, beta-amyloid proteins, DNA, and collagen. Created with BioRender.com (accessed on 14 November 2024).

Figure 2

RAGE forms oligomers to bind ligands, interacting with negatively charged molecules. Upon ligand binding, conformational changes occur in the receptor’s cytoplasmic tail, activating signaling adaptors such as diaphanous-1 (Dia1), extracellular signal-regulated kinase (ERK1/2), and protein kinase C (PKC). Dia1 subsequently activates small GTPases like Ras, Cdc42, and Rac1, which stimulate NF-κB signaling via the ERK1/2 and p38 MAPK pathways. NF-κB activation may also occur through the PI3K/Akt pathway, often triggered by reactive oxygen species (ROS) generated during RAGE signaling. Additionally, Dia1 can engage the JAK/STAT pathway, activating both NF-κB and interferon-stimulated response elements (ISRE), amplifying the inflammatory response. These cascades result in pro-inflammatory cellular changes and chemotaxis, recruiting additional inflammatory cells. Created with BioRender.com (accessed on 14 November 2024).

Figure 3

Comparison of RAGE-deficient and wild-type mice responses to subcutaneous Staphylococcus aureus injection reveals that RAGE facilitates distant bacterial migration and exacerbates local tissue damage during infection (↑—increase, ↓—decrease). Conversely, RAGE activation in infection-related wounds may support the healing process, indicating a dual role for the receptor depending on context. Created with BioRender.com (accessed on 14 November 2024).

Figure 4

Overview of RAGE pathway involvement in wound healing (↑—increase, ↓—decrease). The excessive accumulation of AGEs in the skin disrupts fibril formation and scar elasticity, leading to increased tissue contraction. AGEs induce fibroblast apoptosis and cause cell cycle arrest, while also contributing to RAGE overexpression in fibroblasts. This activates signaling pathways such as ERK1/2, MAPK, and NF-κB, promoting pro-inflammatory cytokine secretion (e.g., TNF-α and IL-8). RAGE activation enhances extracellular matrix (ECM) production, including collagen types I and III, and stimulates matrix metalloproteinases (MMPs), impacting tissue remodeling and fibrosis. Created with BioRender.com (accessed on 14 November 2024).

Figure 5

The RAGE pathway can be inhibited at three key intervention points: blocking RAGE ligands, inhibiting the receptor itself, and silencing the RAGE gene. Blue boxes highlight these intervention points, while red boxes illustrate various potential inhibitors of the RAGE pathway. Additional therapies can indirectly suppress contributing signaling pathways, providing complementary strategies for RAGE pathway inhibition. Created with BioRender.com (accessed on 14 November 2024).