DYSREGULATION OF GASTROINTESTINAL RAGE (RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS) EXPRESSION IN A SPONTANEOUS ANIMAL MODEL OF INFLAMMATORY BOWEL DISEASE

Abstract

Abstract The receptor for advanced glycation end products (RAGE), a pattern recognition receptor, plays a role in chronic inflammation. Abrogation of proinflammatory RAGE signaling by ligand binding (e.g., S100/calgranulins) to soluble RAGE decoy (sRAGE) is a promising novel therapeutic avenue for chronic inflammatory diseases, such as inflammatory bowel disease (IBD). However, the opportunities for studying S100/calgranulin-RAGE pathways in conventional animal models are limited due to species differences in the expression and function of S100/calgranulins (e.g., lack of the S100A12 protein in rodents). The pathogenesis of IBD in dogs involves dysregulated innate immune responses, and serum sRAGE levels are decreased in canine IBD and normalize only with clinical remission. Thus, canine IBD may serve as a spontaneous model of IBD for such studies. This study evaluated gastrointestinal mucosal RAGE expression in dogs with IBD and the binding of RAGE to canine S100/calgranulin ligands. Epithelial RAGE expression was quantified in endoscopic gastrointestinal (i.e., gastric, duodenal, ileal, and colonic) biopsies from 12 dogs with IBD and 9 healthy control dogs by laser scanning microscopy. RAGE expression was compared between both groups of dogs and was tested for an association with patient characteristics, clinical variables, histologic lesion severity, and biomarkers of extra-gastrointestinal disease, systemic or gastrointestinal inflammation, function, or protein loss. Statistical significance (non-parametric tests) was set at p<0.05. RAGE:S100/calgranulin binding was investigated by immunoassay and electrophoretic techniques. RAGE expression was detected in all biopsies evaluated. Epithelial RAGE expression in the duodenum and colon was significantly higher in dogs with IBD than in healthy controls (p<0.04), with a trend for overexpression in the ileum, underexpression in the stomach, and a general shift towards more basal than apical epithelial RAGE expression. Serum sRAGE was correlated with duodenal RAGE expression. Several histologic (structural and inflammatory) lesion criteria and markers of gastrointestinal inflammation or protein loss were related to segmental RAGE expression (all p<0.04). In vitro, canine RAGE:S100A12 binding appeared more pronounced than RAGE:S100A8/A9 binding. Alterations in the epithelial expression of RAGE along the gastrointestinal tract provide evidence for a dysregulated sRAGE/RAGE axis as a characteristic of canine IBD. S100/calgranulin (S100A8/A9 and S100A12) proteins are ligands for RAGE in dogs. The role of RAGE signaling in IBD pathogenesis and its potential for developing novel targeted therapeutics warrants further exploration. Furthermore, canine IBD is a suitable spontaneous model for human IBD that may benefit further research into pathway-specific IBD treatment options that target the sRAGE/RAGE axis.