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Aberrant expression of neutrophil and macrophage‐related genes in a murine model for human neutrophil‐specific granule deficiency
Author(s) -
Gombart Adrian F.,
Krug Utz,
O’Kelly James,
An Eun,
Vegesna Vijaya,
Koeffler H. Phillip
Publication year - 2005
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0504286
Subject(s) - biology , chemokine , scavenger receptor , innate immune system , microbiology and biotechnology , signal transduction , ccr1 , immune system , chemokine receptor , immunology , lipoprotein , biochemistry , cholesterol
Neutrophil‐specific granule deficiency involves inheritance of germline mutations in the CCAAT/enhancer‐binding protein ε (C/EBPE) gene. Humans and mice lacking active C/EBPε 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/EBPε−/− 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/EBPε 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/EBPε−/− mice correlated with reduced total cholesterol levels in these mice before and after maintenance on a high‐fat diet. Also, C/EBPε‐deficient macrophages showed a reduced capacity to accumulate lipids. In summary, dysregulation of numerous, novel C/EBPε target genes impairs innate immune response and possibly other important biological processes mediated by neutrophils and macrophages.