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

of pancreatic lymphocyte infiltration which was restored upon re-introduction of DCs and macrophages [88, 89]. Following the depletion of macrophages, lymphocytes are also unable to initiate T1DM in the NOD-SCID adoptive transfer mouse model [90].

Monocytes, macrophages as well as RAGE- ligands axis are known players in the diabetic vascular complications. RAGE expression is associated with activation of both monocytes and macrophages which has been well explored in diabetes complications such as atherosclerosis [91, 92] and kidney disease [93–95]. Furthermore hypoxic environments can enhance monocyte adhesion and chemotaxis as well as induction of macrophage proinflammatory phenotype mediated by RAGE activity [96]. Furthermore, HMGB1 signaling through RAGE promotes secretion of IL-10 by M2 macrophages is of particular significance in the hypoxic environments of certain metastatic tumors [97]. In the individuals with T1DM suffering from retinopathy and nephropathy, the mRNA RAGE expression in monocytes was significantly reduced compared to controls. Upon exposure of monocyte cultures to glyceraldehyde-derived AGEs both mRNA and protein levels of RAGE were decreased [98]. This was a surprising result considering that upregulation of RAGE is associated with proinflammatory processes. Another study highlighted increased RAGE expression and activation in the M2 macrophages necessary for tumor vascularization and invasion [99]. Despite significant gaps in our knowledge there is unequivocal evidence that upregulation of RAGE upon binding its ligands leads to activation of proinflammatory cascades which likely impart detrimental effects in autoimmunity.

RAGE is an immunoglobulin type receptor comprised of a ligand binding V-type domain, C1 and C2 domains, transmembrane and cytoplasmic domains. C-truncated soluble RAGE can result from proteolytic cleavage or endogenous splicing of the RAGE gene, *AGER*. RAGE as a pattern recognition receptor can bind a wide range of ligands including AGEs, HMGB1, S100 calgranulins. Commonly, upon ligation downstream signaling via Diaphenous-1 and JAK-STAT pathways ROS production and NF-κB activation occurs stimulating inflammatory processes [11]. In T1DM, RAGE is postulated as important for various mechanisms of central and peripheral tolerance which fail to suppress the escape and activation of autoreactive T cells. This occurs in the presence of already dampened regulatory mechanisms where both function and number of Tregs are reduced This leads to further activation and expansion of pathogenic islet specific T cells aided by antigen presentation by DCs. CD8+ T cells migrate to pancreatic islets facilitating immune destruction and, pancreatic β-cell death and further formation and release of diabetogenic antigens. Pancreatic β-cells may also act as APCs by presenting MHC class I molecules and engaging with cytotoxic CD8+ T cells [100]. Inflamed and apoptotic β-cells can also release molecules that act as RAGE ligands further perpetuating the inflammatory cascade by maturation and activation of DCs and macrophages leading to pancreatic injury. NK cells can directly engage with β-cells through NKG2D-RAE1 interaction known to cause pancreatic β-cells death [101]. Furthermore, NK cells can release large quantities of cytotoxic granules and HMGB1 that may directly interact with RAGE expressed on β-cells [53]. Similar to NK cells, neutrophils can also release RAGE ligands and interact with other RAGE expressing cells including pancreatic β-cells [61].
