C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice
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C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice. / Kyme, Pierre; Thoennissen, Nils H; Tseng, Ching Wen; Thoennissen, Gabriela B; Wolf, Andrea J; Shimada, Kenichi; Krug, Utz O; Lee, Kunik; Müller-Tidow, Carsten; Berdel, Wolfgang E; Hardy, W David; Gombart, Adrian F; Koeffler, H Phillip; Liu, George Y.
In: J CLIN INVEST, Vol. 122, No. 9, 09.2012, p. 3316-29.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice
AU - Kyme, Pierre
AU - Thoennissen, Nils H
AU - Tseng, Ching Wen
AU - Thoennissen, Gabriela B
AU - Wolf, Andrea J
AU - Shimada, Kenichi
AU - Krug, Utz O
AU - Lee, Kunik
AU - Müller-Tidow, Carsten
AU - Berdel, Wolfgang E
AU - Hardy, W David
AU - Gombart, Adrian F
AU - Koeffler, H Phillip
AU - Liu, George Y
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
KW - Acetylation
KW - Animals
KW - Anti-Bacterial Agents
KW - CCAAT-Enhancer-Binding Proteins
KW - Cells, Cultured
KW - Gene Expression
KW - Gene Expression Regulation
KW - Histones
KW - Humans
KW - Immunity, Innate
KW - Macrophages
KW - Mice
KW - Mice, Knockout
KW - Microbial Viability
KW - Neutrophils
KW - Niacinamide
KW - Promoter Regions, Genetic
KW - Staphylococcal Skin Infections
KW - Staphylococcus aureus
U2 - 10.1172/JCI62070
DO - 10.1172/JCI62070
M3 - SCORING: Journal article
C2 - 22922257
VL - 122
SP - 3316
EP - 3329
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 9
ER -