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.

The Role of Cutaneous Microbiota Harmony in Maintaining a Functional Skin Barrier

“…Niacinamine (vitamin B 3 ) is combined with emollients in some skin products and it is also employed in culture media for some bacteria. It may have benefit in promoting skin health as it has been shown to inhibit the growth of methicillinresistant S aureus (25) .…”

LPS independent activation of the pro-inflammatory receptor Trem1 by C/EBPε in granulocytes

“…Interestingly, the 177 genes activated by C/EBPε in Gr-1hi cells are significantly enriched in gene ontology categories involved in inflammation and immune response (Supplementary Figure 2B). Moreover, our list of C/EBPε targets included lactoferrin ( Ltf ), Camp , neutrophil collagenase ( Mmp8 ), and neutrophil gelatinase-associated lipocalin ( Ngal or Lcn2 ) which are well-characterized C/EBPε targets, indicating the validity of our approach of combining the RNA-Seq and ChIP-Seq15162324.…”

“…It can activate the full spectrum of effector functions of granulocytes including the release of inflammatory cytokines, degranulation, phagocytosis, and the oxidative burst183940. Trem1/3 double KO mice displayed a high mortality rate by 24 hours after Gram-negative bacterial challenge secondary to dysregulation of cytokine production, and a migration defect of granulocytes through respiratory epithelial cells41, which is similar to C/EBPε KO mice16. The finding that both C/EBPε KO mice and Trem1/3 double KO mice exhibit increased susceptibility to infection indicates their overlapping function towards innate immunity mediated by granulocytes.…”

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

“…Vitamin B3 (nicotinamide) pretreatment of human whole blood increased C/EBPε levels and clearance of S. aureus (as well as P. aeruginosa and K. pneumoniae ) attributable to enhance phagocytic cell function. Treating mice with vitamin B3 also decreased S. aureus bacterial loads in kidneys and spleens [71]. Finally, in cystic fibrosis, mutations in the CFTR ion transporter lead to abnormal mucus dynamics, persistent bacterial pneumonia, and chronic debilitating loss of pulmonary function.…”