Macrophage epoxygenase determines a profibrotic transcriptome signature.
Macrophage epoxygenase determines a profibrotic transcriptome signature.
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DOI：
10.4049/jimmunol.1402979
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发表时间：
2015-05-15
期刊：
影响因子：
--
通讯作者：
Aitman TJ
中科院分区：
文献类型：
--
作者：
Behmoaras J;Diaz AG;Venda L;Ko JH;Srivastava P;Montoya A;Faull P;Webster Z;Moyon B;Pusey CD;Abraham DJ;Petretto E;Cook TH;Aitman TJ
环氧合酶属于细胞色素P450家族，并且它们产生已知具有抗炎作用的环氧二十碳三烯酸（Epoxyeicosatrienoic acids，ECO 3），但是关于它们在巨噬细胞功能中的作用知之甚少。通过高通量测序的RNA（RNA-seq）在原代巨噬细胞来自啮齿动物和人类，我们建立了这些细胞中的相对表达的环氧酶。锌指核酸酶介导的主要大鼠巨噬细胞表氧化酶Cyp 2 j 4（人CYP 2 J2的直向同源物）的靶向基因缺失导致EET合成减少。Cyp 2 j 4 −/−巨噬细胞具有相对增加的PPARγ水平，并显示促纤维化转录组，显示主要参与细胞外基质的特定基因子集（260个转录物）的过度表达，其中纤连蛋白是表达最丰富的转录物。人和大鼠原代巨噬细胞中纤连蛋白的表达受环氧酶活性的控制。与体外研究结果一致，Cyp 2 j 4 −/−大鼠在肾脏单侧输尿管梗阻（UUO）后显示I型胶原蛋白上调，定量蛋白质组学分析（LC-MS/MS）显示这些大鼠实验诱导的新月体肾小球肾炎导致肾脏I型胶原蛋白和纤连蛋白蛋白丰度增加。总之，这些结果将大鼠环氧合酶Cyp 2 j 4鉴定为促纤维化巨噬细胞转录组的决定因素，其可能在取决于巨噬细胞功能的各种炎症状况中具有影响。
Epoxygenases belong to the cytochrome P450 family and they generate epoxyeicosatrienoic acids (EETs) known to have anti-inflammatory effects but little is known about their role in macrophage function. By high-throughput sequencing of RNA (RNA-seq) in primary macrophages derived from rodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (orthologue of human CYP2J2), resulted in reduced EET synthesis. Cyp2j4−/− macrophages have relatively increased PPARγ levels and show a pro-fibrotic transcriptome, displaying over-expression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript. Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the in vitro findings, Cyp2j4−/− rats show up-regulation of type I collagen following unilateral ureter obstruction (UUO) of the kidney and quantitative proteomics analysis (LC-MS/MS) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a pro-fibrotic macrophage transcriptome that could have implications in various inflammatory conditions depending on macrophage function.
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影响因子：
4.4
作者：
Hull RP;Srivastava PK;D'Souza Z;Atanur SS;Mechta-Grigoriou F;Game L;Petretto E;Cook HT;Aitman TJ;Behmoaras J
通讯作者：
Behmoaras J
DOI：
10.1161/hypertensionaha.114.03884
发表时间：
2014-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Abraham NG;Sodhi K;Silvis AM;Vanella L;Favero G;Rezzani R;Lee C;Zeldin DC;Schwartzman ML
通讯作者：
Schwartzman ML
影响因子：
4.4
作者：
Martinez, Fernando O.;Gordon, Siamon;Mantovani, Alberto
通讯作者：
Mantovani, Alberto
影响因子：
5.6
作者：
Mosha, Karni S.;Zeldin, Darryl C.;Tyagi, Suresh C.
通讯作者：
Tyagi, Suresh C.
影响因子：
4.8
作者：
Deng, Yangmei;Edin, Matthew L.;Lee, Craig R.
通讯作者：
Lee, Craig R.