The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases
The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases
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DOI：
10.1038/s41385-018-0119-z
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发表时间：
2019-02-01
影响因子：
8
通讯作者：
Vignal, C.
中科院分区：
文献类型：
--
作者：
Body-Malapel, M.;Djouina, M.;Vignal, C.
炎症性肠病（IBD）是肠道的慢性炎症性疾病。IBD被认为是由遗传易感患者针对肠道植物群的不适当免疫应答引起的。这些疾病的确切病因尚不完全清楚，因此治疗依赖于抑制症状，基本上是炎症，而不是治愈疾病。尽管生物制剂，如抗TNF抗体的可用性，一些患者仍然在治疗失败，因此需要新的治疗。晚期糖基化终产物多配体受体（multiligand receptor for advanced glycation end-products，简称AGEs）是一种参与炎症反应和免疫系统激活的模式识别受体。在这里，我们研究了BMPs在肠道炎症中的作用及其作为IBD治疗靶点的潜力。我们发现，与对照组相比，IBD患者的炎症组织中的β-淀粉样蛋白表达上调。与WT小鼠相比，Rage（-/-）小鼠对肠道和结肠炎症发展的敏感性较低。用RAGE特异性抑制剂FPS-ZM 1治疗的WT小鼠经历了不太严重的肠炎和结肠炎。我们证明RAGE可以通过促进氧化应激和内皮活化来诱导肠道炎症，而FPS-ZM 1治疗可以减少氧化应激和内皮活化。我们的研究结果揭示了IBD患者的一个有前途的治疗靶点的信号通路。
Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage(-/-) mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.