Innate immunity plays a central role in the pathogenesis of chronic inflammatory enteropathies (CIE) in dogs, and further evaluation of the innate immune receptor for advanced glycation end-products (RAGE) is warranted. We measured serum concentrations of decoy receptor soluble RAGE (sRAGE) in 102 dogs diagnosed with CIE, and evaluated relationships with clinical disease severity, histologic lesion severity, concentrations of serum C-reactive protein (CRP), and serum and fecal calprotectin, S100A12, and alpha1-proteinase inhibitor (α1PI). Serum sRAGE levels were not associated with clinical disease activity, serum CRP, serum and fecal α1PI, calprotectin, or S100A12 concentrations. Microscopic lesions in the duodenum were more severe in dogs with serum sRAGE concentration ≤ 340 ng/L ( p = 0.013). Serum sRAGE levels were weakly and inversely correlated with the severity of lymphoplasmacytic infiltration in the gastric antrum and duodenum, and with crypt dilation and the neutrophilic infiltrate in the duodenum, in univariate analysis (all p < 0.05), but none of the correlations remained statistically significant after correction for multiple comparisons. Our study confirms that CIE in dogs is associated with decreased serum sRAGE concentrations, suggesting a dysregulated sRAGE/RAGE axis.
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.
Vitamin B
12
(Cobalamin) ist ein wasserlösliches B-Vitamin, das über spezifische Rezeptoren im distalen Dünndarm absorbiert wird
1
,
2
. In der Kleintiergastroenterologie erfährt dieses Vitamin sowohl diagnostisch als auch therapeutisch große Beachtung. Vielfältige Ursachen können zu
Veränderungen im Serum-Cobalaminstatus bei Kleintierpatienten führen
2
, die im Folgenden näher beleuchtet werden.
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