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Macrophage epoxygenase determines a profibrotic transcriptome signature.

Authors: Behmoaras, Jacques  Diaz, Ana Garcia  Venda, Lara  Ko, Jeong-Hun  Srivastava, Prashant  Montoya, Alex  Faull, Peter  Webster, Zoe  Moyon, Ben  Pusey, Charles D  Abraham, David J  Petretto, Enrico  Cook, Terence H  Aitman, Timothy J 
Citation: Behmoaras J, etal., J Immunol. 2015 May 15;194(10):4705-16. doi: 10.4049/jimmunol.1402979. Epub 2015 Apr 3.
Pubmed: (View Article at PubMed) PMID:25840911
DOI: Full-text: DOI:10.4049/jimmunol.1402979

Epoxygenases belong to the cytochrome P450 family. They generate epoxyeicosatrienoic acids, which are known to have anti-inflammatory effects, but little is known about their role in macrophage function. By high-throughput sequencing of RNA 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 (ortholog of human CYP2J2) resulted in reduced epoxyeicosatrienoic acid synthesis. Cyp2j4(-/-) macrophages have relatively increased peroxisome proliferator-activated receptor-γ levels and show a profibrotic transcriptome, displaying overexpression 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 upregulation of type I collagen following unilateral ureter obstruction of the kidney, and quantitative proteomics analysis (liquid chromatography-tandem mass spectrometry) 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 profibrotic macrophage transcriptome that could have implications in various inflammatory conditions, depending on macrophage function.

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CRRD Object Information
CRRD ID: 12904676
Created: 2017-05-17
Species: All species
Last Modified: 2017-05-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.