C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice
Pierre Kyme, … , H. Phillip Koeffler, George Y. Liu
Pierre Kyme, … , H. Phillip Koeffler, George Y. Liu
Published August 27, 2012
Citation Information: J Clin Invest. 2012;122(9):3316-3329. https://doi.org/10.1172/JCI62070.
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Research Article Infectious disease

C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

Abstract

The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPε-deficient mice are severely affected by infection with S. aureus, and C/EBPε deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPε in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPε and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPε-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system.

Authors

Pierre Kyme, Nils H. Thoennissen, Ching Wen Tseng, Gabriela B. Thoennissen, Andrea J. Wolf, Kenichi Shimada, Utz O. Krug, Kunik Lee, Carsten Müller-Tidow, Wolfgang E. Berdel, W. David Hardy, Adrian F. Gombart, H. Phillip Koeffler, George Y. Liu

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Figure 4

NAM selectively enhances neutrophil killing of S. aureus.

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NAM selectively enhances neutrophil killing of S. aureus. (A) Effect o...
(A) Effect of NAM on clearance of S. aureus by human neutrophils. Human neutrophils (n = 3 volunteers) were treated ex vivo with PBS or NAM (1 mM) for 20 hours and then infected with 2.4 × 108 CFU/ml preopsonized S. aureus in a gentamicin protection assay. Surviving intracellular bacteria recovered at indicated times (mean ± SEM) are shown. (B) Effect of NAM on clearance of S. aureus by human peripheral mononuclear cells. Human monocytes (n = 3 volunteers) were treated ex vivo with PBS or NAM (1 mM) for 20 hours and then infected with preopsonized S. aureus. Recovered intracellular bacteria (mean ± SEM) are shown. (C) Effect of NAM on in vivo clearance of S. aureus by WT mice depleted of neutrophils. WT mice (n = 6–9/group) were treated daily with NAM (250 mg/kg/d, i.p.) or with PBS beginning 24 hours prior to systemic (i.p.) infection with ~1 × 107 CFU S. aureus. Neutrophil depletion (or serum control) was performed in parallel. CFU count in spleens and kidneys of WT mice at 48 hours p.i. Dashed lines indicate limit of detection. (D) Effect of NAM treatment on granulocytosis in WT mice. WT mice (n = 5–12/group/time point) were treated with NAM (250 mg/kg/d, i.p.) or PBS, and CBC with automated differential was performed on blood taken at 24, 48, and 72 hours to determine the population of neutrophils and monocytes. (C and D) Red bars indicate mean. Symbols indicate individual samples. *P < 0.05; **P < 0.01; ***P < 0.001.