Neutrophil Maturation and Survival Is Controlled by IFN-Dependent Regulation of NAMPT Signaling.

Elena Siakaeva,Sharareh Bordbari,Ilona Spyra,Cornelius Kürten,Stephan Lang,Benedikt Höing,Jadwiga Jablonska,Ekaterina Pylaeva

doi:10.3390/ijms20225584

Abstract

Granulocyte-colony stimulating factor (G-CSF)/nicotinamide phosphoribosyltransferase (NAMPT) signaling has been shown to be crucial for the modulation of neutrophil development and functionality. As this signaling pathway is significantly suppressed by type I interferons (IFNs), we aimed to study how the regulation of neutrophil differentiation and phenotype is altered in IFN-deficient mice during granulopoiesis. The composition of bone marrow granulocyte progenitors and their Nampt expression were assessed in bone marrow of type I IFN receptor knockout (Ifnar1-/-) mice and compared to wild-type animals. The impact of NAMPT inhibition on the proliferation, survival, and differentiation of murine bone marrow progenitors, as well as of murine 32D and human HL-60 neutrophil-like cell lines, was estimated. The progressive increase of Nampt expression during neutrophil progenitor maturation could be observed, and it was more prominent in IFN-deficient animals. Altered composition of bone marrow progenitors in these mice correlated with the dysregulation of apoptosis and altered differentiation of these cells. We observed that NAMPT is vitally important for survival of early progenitors, while at later stages it delays the differentiation of neutrophils, with moderate effect on their survival. This study shows that IFN-deficiency leads to the elevated NAMPT expression in the bone marrow, which in turn modulates neutrophil development and differentiation, even in the absence of tumor-derived stimuli.

Highlights

Neutrophils are the most frequent leukocytes in human blood
As neutrophils play a crucial role during tumor development [9,10,11,12], we focused on the regulation of nicotinamide phosphoribosyltransferase (NAMPT) signaling and functionality of neutrophils in IFN deficiency
We have identified an important association between IFN-dependent NAMPT expression and the regulation of neutrophil maturation in mice and human

Summary

Introduction

Neutrophils are the most frequent leukocytes in human blood They mature in the bone marrow and are released to the circulation to exert their multiple roles as effector cells in the innate arm of the immune system. These cells are the earliest to arrive at the site of infection, providing the first line of defense against pathogens. The development of neutrophils in the bone marrow (BM) is tightly regulated They develop from multipotent hematopoietic stem cells (HSCs) that are contained in the LSK (Lin−/Sca-1+/c-Kit+) cell population. The commitment and differentiation of myeloid progenitors to mature neutrophils are strictly controlled by different factors, the most important being granulocyte-colony stimulating factor (G-CSF), known as colony-stimulating factor 3 (CSF 3)

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