All the "RAGE" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses

Abstract

The receptor for advanced glycation endproducts (RAGE) is a pro-inflammatory pattern recognition receptor (PRR) that has been implicated in the pathogenesis of numerous inflammatory diseases. It was discovered in 1992 on endothelial cells and was named for its ability to bind advanced glycation endproducts and promote vascular inflammation in the vessels of patients with diabetes. Further studies revealed that RAGE is most highly expressed in lung tissue and spurred numerous explorations into RAGE's role in the lung. These studies have found that RAGE is an important mediator in allergic airway inflammation (AAI) and asthma, pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), acute lung injury, pneumonia, cystic fibrosis, and bronchopulmonary dysplasia. RAGE has not yet been targeted in the lungs of paediatric or adult clinical populations, but the development of new ways to inhibit RAGE is setting the stage for the emergence of novel therapeutic agents for patients suffering from these pulmonary conditions.

Keywords: Asthma; Bronchopulmonary dysplasia; Cystic fibrosis; Pulmonary disease; Receptor for advanced glycation endproducts (RAGE).

Figure 1. Schematic diagram of RAGE signaling pathways

A) RAGE structure is depicted showing its variable domain (V), two constant domains (C), and cytoplasmic tail. B) RAGE ligands are depicted as orange diamonds, and include AGEs, HMGB1, S100/calgranulins, amyloid β, etc. C) Upon ligand binding, intracellular signaling cascades are initiated (see Section “Functions and signaling pathways” for detailed description), which leads to D) transcriptional activation of NF-κB- and STAT-dependent gene transcription. RAGE-dependent activation of NF-κB induces a positive feedback loop by inducing RAGE and NF-kB gene transcription. E) RAGE binds type I and IV collagen, resulting in cell adhesion and cell spreading. F) RAGE binds Mac-1 integrins on leukocytes and RAGE-signaling induces ICAM1/VCAM1 expression, all of which promote leukocyte adhesion.

Figure 2. Summary of RAGE’s known and hypothetical roles in allergic airway inflammation

A) Allergens trigger release of RAGE ligands, which bind to and activate RAGE on type 1 alveolar (AT1) epithelial cells. B) This signaling is suspected to trigger release of IL-33 from type 2 alveolar (AT2) epithelial cells (dotted line). C) IL-33 can activate resident immune cells in the lung and is also released into the circulation to activate ILC2s in the bone marrow. Activated pulmonary Th2 cells and ILC2s produce large amounts of IL-5 and IL-13 to exacerbate allergic airway inflammation and airway hyperresponsiveness. D) RAGE may potentially bind to and recruit ILC2s directly into the lung via interactions with integrins on ILC2s (not yet studied).