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Differential expression of soluble receptor for advanced glycation end-products (sRAGE) in mice susceptible or resistant to chronic colitis

By Michael Bramhall, Kevin Rich, Ajanta Chakraborty, Larisa Logunova, Namshik Han, James Wilson, Catherine Booth, John McLaughlin, Andrew Brass, Sheena M. Cruickshank

Posted 05 Aug 2019
bioRxiv DOI: 10.1101/719310 (published DOI: 10.1093/ibd/izz311)

Aims: Identifying the factors that contribute to chronicity in inflamed colitic tissue is not trivial. However, in mouse models of colitis, we can investigate at preclinical timepoints. We sought to validate murine Trichuris muris infection as a model for identification of factors that promote development of chronic colitis. Methods: We compared preclinical changes in mice with a resolving immune response to T. muris (resistant) versus mice that fail to expel the worms and develop chronic colitis (susceptible). Findings were then validated in healthy controls and patients with suspected or confirmed IBD. Results: The Receptor for Advanced Glycation End Products ( Rage ) was highly dysregulated between resistant and susceptible mice prior to the onset of any pathological signs. Increased soluble RAGE (sRAGE) in the serum and faeces of resistant mice correlated with reduced colitis scores. Mouse model findings were validated in a preliminary clinical study: faecal sRAGE was differentially expressed in patients with active IBD compared with IBD in remission, patients with IBD excluded or healthy controls. Conclusion: Pre-clinical changes in mouse models can identify early pathways in the development of chronic inflammation that human studies cannot. We identified the decoy receptor sRAGE as a potential mechanism for protection against chronic inflammation in colitis in mice and humans. We propose that the RAGE pathway is clinically relevant in the onset of chronic colitis, and that further study of sRAGE in IBD may provide a novel diagnostic and therapeutic target.

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