Crucial role of the melanocortin receptor MC1R in experimental colitis
Crucial role of the melanocortin receptor MC1R in experimental colitis
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DOI：
10.1136/gut.2005.083634
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发表时间：
2006-10-01
期刊：
影响因子：
24.5
通讯作者：
Kucharzik, T.
中科院分区：
文献类型：
--
作者：
Maaser, C.;Kannengiesser, K.;Kucharzik, T.
背景和目标：已知α-促黑素细胞激素（α MSH）发挥抗炎作用，例如在鼠DSS（葡聚糖硫酸钠诱导的）结肠炎中。aMSH的抗炎功能由自身调节环中的黑皮质素1受体（MC 1 R）介导。因此，本研究的目的是确定是否的α MSH-MC 1 R通路的故障导致病情恶化的diseases.Methods：实验性结肠炎诱导小鼠中的MC 1 R基因（MC 1 Re/e），C57 BL/6野生型小鼠，MC 1 Re/e-C57 BL/6骨髓嵌合体的移码突变。通过体重减轻、结肠组织学变化和髓过氧化物酶活性监测炎症过程。此外，MC 1 R的表达进行了分析，在肠上皮细胞。结果：虽然结肠的未处理的MC 1 Re/e出现正常的，在MC 1 Re/e小鼠的DSS-结肠炎的过程中显着加剧，具有显着更高的体重减轻和显着的组织学变化相比，C57 BL/6 WT。炎症最终导致所有MC 1 Re/e死亡，而所有C57 BL/6 WT存活。在由啮齿类柠檬酸杆菌诱导的传染性小鼠结肠炎模型中检测到类似的观察结果。感染的MC 1 Re/e显示感染清除延迟。为了确定缺失的造血细胞表达的MC 1 R是否负责，在MC 1 Re/e-C57 BL/6骨髓嵌合体中诱导DSS结肠炎。接受MC 1 R+骨髓的MC 1 Re/e小鼠表现出与非移植MC 1 Re/e相似的炎症过程。同样，MC 1 R骨髓移植到C57 BL/6 WT小鼠没有导致任何恶化的diseases.Conclusions：这是第一次研究表明MC 1 R在肠道炎症的功能作用。这些数据表明，非造血细胞表达的MC 1 R在宿主对病原性刺激的反应中起关键作用。
Background and aims: alpha-Melanocyte stimulating hormone (alpha MSH) is known to exert anti-inflammatory effects, for example in murine DSS ( dextran sodium sulphate induced) colitis. The anti-inflammatory functions of aMSH are mediated by the melanocortin1-receptor (MC1R) in an autoregulatory loop. The aim of this study was therefore to determine whether a breakdown of the alpha MSH-MC1R pathway leads to worsening of disease.Methods: Experimental colitis was induced in mice with a frameshift mutation in the MC1R gene (MC1Re/e), C57BL/6 wild type mice, and MC1Re/e-C57BL/6 bone marrow chimeras. The course of inflammation was monitored by weight loss, histological changes in the colon, and myeloperoxidase activity. In addition, MC1R expression was analysed in intestinal epithelial cells.Results: While the colon of untreated MC1Re/e appeared normal, the course of DSS-colitis in MC1Re/e mice was dramatically aggravated, with a significantly higher weight loss and marked histological changes compared to C57BL/6WT. The inflammation eventually led to death in all MC1Re/e, while all C57BL/6WT survived. Similar observations were detected in a transmissible murine colitis model induced by Citrobacter rodentium. Infected MC1Re/e showed delayed clearance of infection. To determine whether missing haematopoietic cell expressed MC1R was responsible, DSS colitis was induced in MC1Re/e-C57BL/6 bone marrow chimeras. MC1Re/e mice receiving MC1R+ bone marrow showed a similar course of inflammation to non-transplanted MC1Re/e. Likewise, transplantation of MC1R bone marrow into C57BL/6WT mice did not lead to any worsening of disease.Conclusions: This is the first study to show a functional role of MC1R in intestinal inflammation. The data suggest a pivotal role of non-haematopoietic cell expressed MC1R in the host's response to pathogenic stimuli.