*The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes… DOI: http://dx.doi.org/10.5772/intechopen.108528*

advanced glycation endproducts (AGEs), high mobility group box-1 (HMGB1), S100 proteins, β-amyloid fibrils, and others [11]. Upon binding to its ligands, the cytoplasmic domain associates with adaptor proteins including TIRAP and MyD88 followed by activation of downstream signaling of various pathways including NF-κB and STAT3 (**Figure 1**) [12].

Advanced Glycation Endproducts (AGEs) are canonical RAGE ligands but are low affinity and likely only bind RAGE when increased in concentration [13]. AGEs are formed as the result of non-enzymatic modifications to amino groups on lipids, proteins, peptides, and nucleic acids. Modern industrialization of food, flavor, and color enhancement as well as increased emulsification contribute significantly to formation of AGEs [9, 14, 15]. Prolonged exposure to AGEs has detrimental effects on β-cell function, insulin secretion and sensitivity and disease development in healthy humans and rodents [16]. Moreover, accumulation of AGEs and RAGE is associated with macro and micro vascular complications in diabetic patients [14, 17–19]. In the islet autoantibody positive individuals, the levels of circulating AGEs served as independent predictor for T1DM progression [20]. Chronic exposure of rodents to AGEs led to defects in insulin secretion and beta- cell death as well as defects in mitochondrial function supported by studies in isolated islets and beta cell lines such as MIN6N8. Following the treatment with AGE-lowering agent, the incidence of autoimmune diabetes was reduced in NOD mice [21].

HMGB1 is a non-histone chromosome protein present in all cells and may serve as a transcription factor in proinflammatory conditions [22]. Both RAGE and toll-like receptor 4 (TLR4) have been reported to serve as HMGB1 receptors, although SPR binding studies suggest that HMGB1 only binds to RAGE if associated with DNA fragments. Therapeutic potential of HMGB1 blockade has been shown in NOD mice, reducing T1DM incidence and autoimmunity [23, 24]. In newly diagnosed children

**Figure 1.** *RAGE cellular expression in immune cells important in T1DM development.*

with T1DM, HMGB1 serum concentrations were significantly higher compared to controls suggesting its potential use as an inflammatory biomarker in the disease progression [25]. More recently, it was proposed that increases in HMGB1 impairs the stability of regulatory T cells (Tregs) in NOD mice and increases production of interferon-γ (IFN-γ). In individuals with T1DM increased levels of serum HMGB1 were directly correlated with increases in IFN-γ production by Tregs. Neutralizing HMGB1 antibody rescued Treg function and suppressed autoimmunity [23]. Furthermore, hyperglycemia may contribute to the release of HMGB1 by antigen presenting, natural killer and endothelial cells as well as necrotic and apoptotic cells leading to augmented autoimmunity [26].

Another set of proteins identified as RAGE ligands is S100 calgranulin family containing over 20 members with S100A8/9 and S100B binding RAGE [27]. Although their major site of manufacture is believed to be endothelial cells, they are known to be expressed by myeloid cells such as neutrophils, but expression by lymphocytes has not been reported. This proinflammatory heterodimer is implicated in several conditions including inflammatory bowel disease and rheumatoid arthritis. Furthermore, S100A8/A9 expression is associated with tumorigenesis, suppression of DC function and accumulation of myeloid-derived suppressor cells (MDSCs) [28].

RAGE can exist as both transmembrane protein and a truncated soluble form (sRAGE). The latter is present in serum and is postulated to act as a decoy receptor by competitively binding RAGE ligands and preventing downstream signaling [11, 12]. RAGE expression tends to be low in most tissues except for the skin and alveolar epithelial cells in the lung [29]. RAGE is expressed on a number of immune cells such as T lymphocytes, neutrophils, antigen presenting cells (APCs) including macrophages, dendritic cells (DCs) and B cells as well as endothelial cells [30]. The precise role of RAGE in these cell populations as well its ability to influence cell-cell interactions and behavior still eludes us. However, RAGE continues to serve as one of the major players in inflammatory and autoimmune conditions creating a perfect opportunity to investigate these links.
