Relation between NOD2 genotype and changes in innate signaling in Crohn's disease on mRNA and miRNA levels.
Relation between NOD2 genotype and changes in innate signaling in Crohn's disease on mRNA and miRNA levels.
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DOI：
10.1038/s41525-016-0001-4
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发表时间：
2017
影响因子：
5.3
通讯作者：
Nielsen OH
中科院分区：
文献类型：
--
作者：
Chen Y;Salem M;Boyd M;Bornholdt J;Li Y;Coskun M;Seidelin JB;Sandelin A;Nielsen OH
克罗恩病与致病重要性的先天免疫反应改变有关。这种改变的反应可能与NOD2(核苷酸结合寡聚化结构域包含蛋白2)基因的功能缺失有关，但也与转录和转录后调节层的变化有关，包括microRNA的活性。在这里，我们通过研究单核细胞对NOD2激动剂胞浆二肽的转录和转录后活性来表征NOD2基因和炎症介导的先天信号变化之间的联系，这些细胞来自健康对照组和具有和不具有NOD2功能丧失多态性的克罗恩病患者。我们检测了这些受试者单核细胞在胞浆二肽刺激下的基因和microRNAs的表达。基因表达谱主要区分实际的胞壁二肽反应，而不是基因型。在没有NOD2突变的克罗恩病患者中发现了一种高反应性表型，其特征是细胞因子受体上调和microRNA表达普遍下调。相反，microRNA的表达可以确定受试者组之间的基因型特异性差异，但在胞壁酰二肽治疗后几乎没有变化。只有两个microRNAs显示了胞壁酰二肽诱导的反应，其中包括miR-155，它被发现调节多个基因，其宿主基因是胞壁酰二肽反应最高的基因之一。在内毒素和大肠杆菌治疗后，NOD2突变的克罗恩病患者中MIR-155表达上调，但经胞壁酰二肽治疗后上调显著减少。虽然具有NOD2突变的克罗恩病患者平均表现出较低的胞浆二肽反应，但队列显示出很大的个体差异：一小部分患者的炎症反应在基因和miR-155调节水平上几乎与野生型患者相当。克罗恩病患者的遗传学影响了他们失调免疫反应的分子驱动因素。一些患有克罗恩病的人在NOD2基因上存在突变，NOD2基因编码一种病原体识别受体，该受体与一种名为胞壁二肽(MDP)的分子结合。为了更好地了解NOD2的变化如何导致肠道炎症的易感性增加，来自丹麦哥本哈根大学和赫列夫医院的Yun Chen和Mohammad Salem及其同事分析了来自健康对照组和具有和不具有NOD2突变的克罗恩病患者的血细胞中基因和小的、调节的microRNAs的表达模式。他们将细胞暴露在MDP下，发现尽管基因活性作为反应发生了戏剧性的变化，但无论遗传因素如何，受试者之间的差异很小。相反，microRNA的表达显示出不受MDP治疗影响的特定基因型的差异。这些发现强调了microRNAs在克罗恩病中的重要性。
Crohn’s disease is associated with an altered innate immune response of pathogenic importance. This altered response can be associated to loss-of-function polymorphisms in the NOD2 (nucleotide-binding oligomerization domain-containing protein 2) gene, but also changes in transcriptional and post-transcriptional regulatory layers, including microRNA activity. Here, we characterized the link between NOD2 genotype and inflammatory-mediated changes in innate signaling by studying transcriptional and post-transcriptional activity in response to NOD2-agonist muramyl dipeptide in monocytes from healthy controls, and Crohn’s disease patients with and without NOD2 loss-of-function polymorphisms. We measured the expression of genes and microRNAs in monocytes from these subjects after stimulation with muramyl dipeptide. Gene expression profiles mainly distinguished the actual muramyl dipeptide response, but not the genotype. A hyper-responsive phenotype was found in Crohn’s disease patients without NOD2 mutations, characterized by upregulated cytokine receptors and general downregulation of microRNA expression. Conversely, microRNA expression could identify genotype-specific differences between subject groups but exhibited little change upon muramyl dipeptide treatment. Only two microRNAs showed muramyl dipeptide-induced response, including miR-155, which was found to regulate multiple genes and whose host gene was one of the highest muramyl dipeptide responders. miR-155 was upregulated in Crohn’s disease patients with NOD2 mutations following lipopolysaccharide and Escherichia coli treatment, but the upregulation was substantially reduced upon muramyl dipeptide treatment. While Crohn’s disease patients with NOD2 mutations on average showed a reduced muramyl dipeptide response, the cohort exhibited large individual variance: a small subset had inflammatory responses almost comparable to wild-type patients on both gene and miR-155 regulatory levels. The genetics of people with Crohn’s disease affects the molecular drivers of their dysregulated immune responses. Some individuals with Crohn’s harbor mutations in the NOD2 gene, which encodes a pathogen recognition receptor that binds to a molecule called muramyl dipeptide (MDP). To better understand how alternations in NOD2 can lead to increased susceptibility to gut inflammation, Yun Chen, Mohammad Salem and colleagues from the University of Copenhagen and Herlev Hospital, Denmark, analyzed the expression patterns of both genes and small, regulatory microRNAs in blood cells from healthy controls and from Crohn’s patients with and without NOD2 mutations. They exposed the cells to MDP, and saw that although gene acticity changed dramatically as a response, there was little difference between subjects, regardless of genetics. Conversely, microRNA expression showed genotype-specific differences that weren not impacted by MDP treatment. The findings underscore the importance of microRNAs in Crohn’s disease.
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影响因子：
29.4
作者：
Gradel, Kim O.;Nielsen, Hans L.;Nielsen, Henrik
通讯作者：
Nielsen, Henrik
DOI：
10.1073/pnas.1116125109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Koch, Manuel;Mollenkopf, Hans-Joachim;Meyer, Thomas F.
通讯作者：
Meyer, Thomas F.
miR-155 对炎症巨噬细胞转录特征的控制。
影响因子：
3.7
作者：
Jablonski KA;Gaudet AD;Amici SA;Popovich PG;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
14.9
作者：
Hsu SD;Tseng YT;Shrestha S;Lin YL;Khaleel A;Chou CH;Chu CF;Huang HY;Lin CM;Ho SY;Jian TY;Lin FM;Chang TH;Weng SL;Liao KW;Liao IE;Liu CC;Huang HD
通讯作者：
Huang HD
影响因子：
3.4
作者：
Moreira, Lilian O.;El Kasmi, Karim C.;Murray, Peter J.
通讯作者：
Murray, Peter J.