CCAAT/Enhancer Binding Protein ɛ Is Critical for Effective Neutrophil-Mediated Response to Inflammatory Challenge

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Abstract
Targeted mutation of CCAAT/enhancer binding protein (C/EBP) ɛ in mice results in early death, primarily due to spontaneous infection with Pseudomonas aeruginosa. Functional analysis of C/EBPɛ-deficient neutrophils, in an in vivo model of peritoneal inflammation, shows multiple defects. Reduction of phagocytotic killing by C/EBPɛ-deficient neutrophils is a result of decreased uptake of opsonized bacteria as well as little to no expression of secondary granule proteins. Abnormalities in neutrophil migration detected in a chemical peritonitis model are likely secondary to abnormal CD11b integrin and L-selectin expression on C/EBPɛ-deficient neutrophils. Alterations in neutrophil cytokine expression in response to inflammation show decreased levels of interleukin-1 receptor antagonist (IL-1Ra) and increased levels of tumor necrosis factor- (TNF-) expression by C/EBPɛ-deficient neutrophils. Additionally, TNF- expression is increased in nonactivated, circulating C/EBPɛ-deficient neutrophils. Overall, C/EBPɛ-deficient neutrophils are severely functionally impaired, evoking an abnormal microenvironment, which may contribute to the loss of normal responses to inflammatory stimuli. Similarities between the C/EBPɛ-deficient mouse model and the human disease, specific granule deficiency, will be discussed.