RGD Reference Report - Macrophage epoxygenase determines a profibrotic transcriptome signature. - Rat Genome Database

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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.
RGD ID: 12904676
Pubmed: PMID:25840911   (View Abstract at PubMed)
PMCID: PMC4417646   (View Article at PubMed Central)
DOI: DOI:10.4049/jimmunol.1402979   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CYP2J2Humannephritis  ISOCyp2j4 (Rattus norvegicus) RGD 
Cyp2j4Ratnephritis  IMP  RGD 
Cyp2j4em1SageRatnephritis  IMP  RGD 
Cyp2j9Mousenephritis  ISOCyp2j4 (Rattus norvegicus) RGD 
WKY-Cyp2j4em1Sage/TjaRatnephritis  IMP  RGD 
CYP2J2Humanureteral obstruction  ISOCyp2j4 (Rattus norvegicus) RGD 
Cyp2j4Ratureteral obstruction  IMP  RGD 
Cyp2j4em1SageRatureteral obstruction  IMP  RGD 
Cyp2j9Mouseureteral obstruction  ISOCyp2j4 (Rattus norvegicus) RGD 
WKY-Cyp2j4em1Sage/TjaRatureteral obstruction  IMP  RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cyp2j4Ratnegative regulation of collagen biosynthetic process  IMP  RGD 
Cyp2j4Ratnegative regulation of peroxisome proliferator activated receptor signaling pathway  IMP  RGD 
Cyp2j4Ratpositive regulation of tumor necrosis factor production  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp2j4  (cytochrome P450, family 2, subfamily j, polypeptide 4)
Cyp2j4em1Sage  (cytochrome P450, family 2, subfamily j, polypeptide 4, ZFN induced mutant 1, Sage)

Genes (Mus musculus)
Cyp2j9  (cytochrome P450, family 2, subfamily j, polypeptide 9)

Genes (Homo sapiens)
CYP2J2  (cytochrome P450 family 2 subfamily J member 2)

WKY-Cyp2j4em1Sage/Tja  (NA)

Objects referenced in this article
Gene Gh1 growth hormone 1 Rattus norvegicus

Additional Information