Role of the Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Inflammatory Responses

Abstract

Since its discovery in 1992, the receptor for advanced glycation end products (RAGE) has emerged as a key receptor in many pathological conditions, especially in inflammatory conditions. RAGE is expressed by most, if not all, immune cells and can be activated by many ligands. One characteristic of RAGE is that its ligands are structurally very diverse and belong to different classes of molecules, making RAGE a promiscuous receptor. Many of RAGE ligands are damaged associated molecular patterns (DAMPs) that are released by cells under inflammatory conditions. Although RAGE has been at the center of a lot of research in the past three decades, a clear understanding of the mechanisms of RAGE activation by its ligands is still missing. In this review, we summarize the current knowledge of the role of RAGE and its ligands in inflammation.

Keywords: DAMP; RAGE; S100; inflammation; stress.

Figure 1

RAGE is a transmembrane protein with an extracellular part consisting of three Ig-fold domains, a variable-type (V-domain) and two constant-type domains (C1 and C2), a single-pass transmembrane domain, and a cytosolic tail. The most common RAGE isoform is full-length RAGE. Other important isoforms are the N-truncated form and the two soluble forms of the receptor ectodomain. Endogenously secreted esRAGE is a splice variant of RAGE. sRAGE is generated by proteolytic clipping following the activation of membrane proteases.

Figure 2

Overview of the RAGE-dependent signaling pathways. Binding of ligands to RAGE leads to the activation of MEK/ERK, PI3K/AKT, or JAK, or the activation of NADPH oxidase (NADPHOX) with the resulting production of reactive oxygen species (ROS), leading to the translocation and activation of several transcription factors (NF-κB, AP-1, STAT3) that promote the transcription of pro-inflammatory genes. RAGE activation results in RAGE upregulation through a NF-κB-dependent positive feedback loop, because of the presence of functional NF-κB binding sites in the RAGE promotor [39,44]. Most RAGE ligands bind to the V domain of RAGE. RAGE activation by its ligands can be inhibited by the soluble form of the receptor, anti-RAGE antibodies, and small molecule inhibitors.

Figure 3

RAGE and its ligands in dendritic cells (DC) and T cells. AGEs stimulate the maturation of DCs and enhance their abilities to stimulate T cells and upregulate RAGE expression [62,63]. HMGB1 released from DCs acts on RAGE to promote functional polarization of T cells [53]. RAGE activation by HMGB1 in DCs results in the differentiation of naive T cells into Th2 and Th17 [54]. RAGE activation by HMGB1 can also result in the imbalance between Treg and Th17 in asthma [57]. RAGE activation by S100B results in the differentiation of naive T cells into Th1 and Th17 in a mouse model of Myasthena Gravis [220].

Figure 4

RAGE and its ligands in macrophages. RAGE activation by AGEs stimulates the M2 to M1 polarization of macrophages and plays a role in the progression of diabetic polyneuropathy [235,236]. LPS/RAGE plays a role in sepsis though the secretion of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) [239]. S100A12/RAGE stimulates the migration of mononuclear phagocytes, the secretion of pro-inflammatory cytokines (IL-1β and TNF-α) by macrophages, and the proliferation of PMBC [4]. AGE/RAGE activation results in reduced expression of the ABCA1 and ABCG1 cholesterol transporters in diabetic macrophages [240]. HMGB1/LPS complexes stimulate macrophages [65]. HMGB1/nucleic acid complexes regulate the activation and termination of inflammasomes in a RAGE-dependent manner, and can also trigger cell death [71,72]. RAGE interaction with PS in macrophages stimulates phagocytosis [141,142]. HMGB1 promotes inflammation when in a complex with LPS, IL-1β, or nucleic acids [17,65,135,241]. RAGE promotes the internalization of HMGB1/LPS and the delivery of LPS intracellular caspase 11, resulting in pyroptosis [70]. C1q interacts with RAGE and enhances phagocytosis [14]. In a complex with HMGB1, C1q promotes the resolution of inflammation [73]. RAGE mediates HMGB1-/LPS-dependent pyroptosis [68,70]. RAGE mediates the secretion of (IL-1β, IL-6, TNF-α) in macrophages in a mouse model of obese mice [242]. RAGE mediates myocardial fibrosis by recruiting M2 macrophages [231].

Figure 5

RAGE and its ligands in microglia. Amyloid β mediates the production of the pro-inflammatory cytokines IL-1β and TNF-α by microglia in a RAGE-dependent manner, leading to neuroinflammation [78]. S100B stimulates the polarization of microglial cells into M1 in mouse models of cerebral ischemia and multiple sclerosis [93,212]. In mouse models of brain ischemia, HMGB1 activates microglial RAGE, resulting in the expression of the pro-inflammatory cytokines IL-1β, TNF-α, and Il-6 [244,245].

Figure 6

RAGE and its ligands in neutrophils. AGE/RAGE mediates neutrophil dysfunction, adhesion, and migration [267,268,269]. S100A9/RAGE elicits NET formation in neutrophils [270]. S100A12 released from neutrophils activates RAGE in human bronchial epithelial cells, resulting in mucous metaplasia [56]. S100A8/A9 released from neutrophils interacts with RAGE on cardiac fibroblasts, resulting in the migration of monocytes and cardiac fibroblasts and inflammation-induced cardiac injury [55].

Figure 7

RAGE and its ligands in eosinophils and basophils. S100B/RAGE stimulates the secretion of S100A8/A9, the upregulation of RAGE, and cell survival [185]. RAGE mediates IL-33 release from epithelial cells, and the recruitment of Th2 and ILC2 cells to the site of inflammation in inflamed airways. In addition, RAGE mediates the activation of the signal transducer and activator of transcription 6 (STAT6), resulting in airway inflammation and mucus metaplasia [274,275]. S100A8/A9 acts in an autocrine manner to further amplify RAGE signaling [275]. HMGB1 stimulates the degranulation and migration of eosinophils [273].