Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis.
Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis.
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DOI：
10.4049/jimmunol.1103031
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发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Kretzler M
中科院分区：
文献类型：
--
作者：
Berthier CC;Bethunaickan R;Gonzalez-Rivera T;Nair V;Ramanujam M;Zhang W;Bottinger EP;Segerer S;Lindenmeyer M;Cohen CD;Davidson A;Kretzler M
狼疮性肾炎（LN）是SLE的一种严重表现。小鼠LN模型的治疗研究并不总是预测人类治疗试验的结果，这引起了人们对这些临床前模型与人类相关性的担忧。在这项研究中，我们使用了一个公正的转录网络的方法来定义在分子方面的相似性和三个狼疮模型和人类LN之间的差异。使用自然语言处理和自动启动子分析生成全基因组基因表达网络，并通过次优图匹配在物种之间进行比较。这三种鼠模型和人LN具有共同和独特的特征。20个共同共享的网络节点反映了免疫细胞浸润/激活、内皮细胞激活/损伤和组织重塑/纤维化的关键病理过程，其中巨噬细胞/树突状细胞激活是占主导地位的跨物种共享转录途径。独特的节点反映了三种小鼠品系之间浸润细胞的数量和类型以及重塑程度的差异。为了确定人LN中单核吞噬细胞衍生的途径，将分离的NZB/W肾单核细胞中激活的基因集与人LN肾谱进行比较。可见组织隔室特异性巨噬细胞活化模式，NFκB1和PPARγ分别作为肾小管间质和肾小球网络中的主要调节节点。我们的研究定义了哪些病理过程在小鼠模型的LN重演的关键转录过程中活跃的人LN，并表明有单核吞噬细胞浸润不同的肾脏微环境之间的功能差异。
Lupus nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these pre-clinical models. In this study we used an unbiased transcriptional network approach to define in molecular terms similarities and differences between three lupus models and human LN. Genome wide gene expression networks were generated using natural language processing and automated promoter analysis and compared across species via suboptimal graph matching. The three murine models and human LN share both common and unique features. The 20 commonly shared network nodes reflect the key pathologic processes of immune cell infiltration/activation, endothelial cell activation/injury and tissue remodeling/fibrosis, with macrophage/dendritic cell activation as a dominant cross-species shared transcriptional pathway. The unique nodes reflect differences in numbers and types of infiltrating cells and degree of remodeling between the three mouse strains. To define mononuclear phagocyte derived pathways in human LN, gene sets activated in isolated NZB/W renal mononuclear cells were compared with human LN kidney profiles. A tissue compartment specific macrophage activation pattern was seen, with NFκB1 and PPARγ as major regulatory nodes in the tubulointerstitial and glomerular networks respectively. Our study defines which pathologic processes in murine models of LN recapitulate the key transcriptional processes active in human LN and suggests that there are functional differences between mononuclear phagocytes infiltrating different renal microenvironments.
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Fcgamma受体介导的巨噬细胞中缺乏SRC家族酪氨酸激酶HCK，FGR和Lyn的吞噬作用。
影响因子：
15.3
作者：
Fitzer-Attas, C J;Lowry, M;Crowley, M T;Finn, A J;Meng, F;DeFranco, A L;Lowell, C A
通讯作者：
Lowell, C A
DOI：
10.4049/jimmunol.1001983
发表时间：
2011-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chang A;Henderson SG;Brandt D;Liu N;Guttikonda R;Hsieh C;Kaverina N;Utset TO;Meehan SM;Quigg RJ;Meffre E;Clark MR
通讯作者：
Clark MR
DOI：
10.1159/000319241
发表时间：
2011-01-01
期刊：
EXPERIMENTAL MODELS FOR RENAL DISEASES: PATHOGENESIS AND DIAGNOSIS
影响因子：
--
作者：
Grande, Joseph P.
通讯作者：
Grande, Joseph P.
影响因子：
13.6
作者：
Lee, Sik;Huen, Sarah;Cantley, Lloyd G.
通讯作者：
Cantley, Lloyd G.
影响因子：
82.9
作者：
Chawla, A;Barak, Y;Evans, RM
通讯作者：
Evans, RM