Neutropenia in individuals with a congenital defect or patients with cancer who are undergoing chemotherapy is generally treated with granulocyte colony-stimulating factor (G-CSF) to restore normal granulopoiesis. Now, Skokowa et al. describe a new pathway involving vitamin B3 (nicotinamide) metabolism to explain how G-CSF triggers granulopoiesis.
When searching for factors that are activated by G-CSF during myeloid-cell differentiation, the authors found that levels of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) were markedly increased in haematopoietic-cell precursors and in the plasma of G-CSF-treated healthy volunteers and patients with congenital neutropenia. NAMPT is involved in the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD+), which has key roles in numerous biological processes through regulating the expression and transcriptional function of the sirtuin family of deacetylases. Accordingly, NAMPT upregulation by G-CSF treatment was accompanied by increased levels of NAD+ and sirtuins. In addition, the key granulocyte-specific transcription factors CCAAT/enhancer-binding protein-α (C/EBPα) and C/EBPβ also showed G-CSF-dependent expression.
In support of the idea that the G-CSF-dependent increase in NAMPT expression promotes neutrophil differentiation, exogenously added NAMPT or lentivirally transduced NAMPT were shown to promote the differentiation of haematopoietic precursors into myeloid-lineage cells in vitro. Conversely, treatment of haematopoietic precursors with a small molecule inhibitor of NAMPT abrogated the G-CSF-triggered increase in NAD+, C/EBPα and C/EBPβ expression and the concomitant granulocytic differentiation.
Given that C/EBPs are known to activate the transcription of genes encoding G-CSF and the G-CSF receptor (G-CSFR), the authors proposed that NAMPT activates an autoregulatory loop, whereby upregulation of NAMPT expression by G-CSF increases NAD+ production, which promotes the overexpression and activation of sirtuins. These, in turn, act on C/EBPs to induce G-CSF and G-CSFR transcription. This proposed mechanism was supported by the findings that sirtuin 1 co-precipitated with C/EBPα and C/EBPβ and that knockdown of sirtuin 1 expression abolished NAMPT-induced G-CSF and G-CSFR transcription.
Finally, based on these in vitro findings, the authors investigated whether vitamin B3 could be used instead of G-CSF as a treatment to boost neutrophil numbers in neutropenic subjects. Treatment of healthy individuals with vitamin B3 resulted in significant increases in neutrophil numbers, which declined following discontinuation of treatment. Similar to G-CSF-treated cells, neutrophils from individuals taking oral vitamin B3 showed increased expression of NAD+, C/EBPα, C/EBPβ and G-CSFR.
So, although it has not yet been tested in individuals with congenital neutropenia, vitamin B3 could prove to be an inexpensive and safe treatment option for this disease.
References
ORIGINAL RESEARCH PAPER
Skokowa, J. et al. NAMPT is essential for the G-CSF–induced myeloid differentiation via a NAD+–sirtuin-1–dependent pathway. Nature Med. 15, 151–158 (2009)
FURTHER READING
Khanna-Gupta, A. & Berliner, N. Vitamin B3 boosts neutrophil counts. Nature Med. 15, 139–141 (2009)
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Bird, L. Vitamin B3: a neutrophil supplement. Nat Rev Immunol 9, 149 (2009). https://doi.org/10.1038/nri2521
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DOI: https://doi.org/10.1038/nri2521