Differential expression of soluble receptor for advanced glycation end-products (sRAGE) in mice susceptible or resistant to chronic colitis
Differential expression of soluble receptor for advanced glycation end-products (sRAGE) in mice susceptible or resistant to chronic colitis
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DOI：
10.1101/719310
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发表时间：
2019-08
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通讯作者：
Michael Bramhall;K. Rich;Ajanta Chakraborty;L. Logunova;Namshik Han;James Wilson;C. Booth;J. Mclaughlin;A. Brass;S. Cruickshank
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作者：
Michael Bramhall;K. Rich;Ajanta Chakraborty;L. Logunova;Namshik Han;James Wilson;C. Booth;J. Mclaughlin;A. Brass;S. Cruickshank
目的确定炎症性结肠炎组织中导致慢性化的因素并不是微不足道的。然而，在结肠炎小鼠模型中，我们可以在临床前时间点进行研究。我们试图验证小鼠鞭虫感染作为一种模型，用于识别促进慢性结肠炎发展的因素。方法我们比较了小鼠对T.小鼠（抗性）与不能排出蠕虫并发展成慢性结肠炎的小鼠（易感）。然后在健康对照和疑似或确诊IBD患者中验证结果。结果在任何病理体征出现之前，晚期糖基化终末产物受体（Rage）在耐药和敏感小鼠之间高度失调。耐药小鼠血清和粪便中可溶性肌酐（s肌酐）的增加与结肠炎评分的降低相关。在初步临床研究中验证了小鼠模型结果：与缓解期IBD、排除IBD的患者或健康对照相比，活动性IBD患者的粪便分泌物表达差异。结论小鼠模型的临床前变化可以识别人类研究无法识别的慢性炎症发展的早期途径。我们确定诱饵受体sleep作为一种潜在的机制，保护免受慢性炎症在小鼠和人类结肠炎。我们认为，SHP通路在慢性结肠炎的发病中具有临床相关性，进一步研究SHP在IBD中的作用可能提供一种新的诊断和治疗靶点。
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.