Aberrant expression of neutrophil and macrophage-related genes in a murine model for human neutrophil-specific granule deficiency.
Neutrophil-specific granule deficiency involves inheritance of germline mutations in the CCAAT/enhancer-binding protein epsilon (C/EBPE) gene. Humans and mice lacking active C/EBPepsilon suffer frequent bacterial infections as a result of functionally defective neutrophils and macrophages. We hypothesized that these defects reflected dysregulation of important immune response genes. To test this, gene expression differences of peritoneally derived neutrophils and macrophages from C/EBPepsilon-/- and wild-type mice were determined with DNA microarrays. Of 283 genes, 146 known genes and 21 expressed sequence tags (ESTs) were down-regulated, and 85 known genes and 31 ESTs were up-regulated in the C/EBP-/- mice. These included genes involved in cell adhesion/chemotaxis, cytoskeletal organization, signal transduction, and immune/inflammatory responses. The cytokines CC chemokine ligand 4, CXC chemokine ligand 2, and interleukin (IL)-6, as well as cytokine receptors IL-8RB and granulocyte-colony stimulating factor, were down-regulated. Chromatin immunoprecipitation analysis identified binding of C/EBPepsilon to their promoter regions. Increased expression for lipid metabolism genes apolipoprotein E (APOE), scavenger receptor class B-1, sorting protein-related receptor containing low-density lipoprotein receptor class A repeat 1, and APOC2 in the C/EBPepsilon-/- mice correlated with reduced total cholesterol levels in these mice before and after maintenance on a high-fat diet. Also, C/EBPepsilon-deficient macrophages showed a reduced capacity to accumulate lipids. In summary, dysregulation of numerous, novel C/EBPepsilon target genes impairs innate immune response and possibly other important biological processes mediated by neutrophils and macrophages.
Gombart
Adrian F
AF
Cedars-Sinai Medical Center, Division of Hematology/Oncology, Burns & Allen Research Institute and David Geffen School of Medicine at University of California Los Angeles, USA. gombarta@csmc.edu
Krug
Utz
U
O'Kelly
James
J
An
Eun
E
Vegesna
Vijaya
V
Koeffler
H Phillip
HP
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D002784:Cholesterol / Q000097:blood / Q000276:immunology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003594:Cytoplasmic Granules / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D008055:Lipids / Q000097:blood / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods
D022762:CCAAT-Enhancer-Binding Proteins; D008055:Lipids; D002784:Cholesterol