Reprogramming Neutrophils into Macrophages

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Blood First Edition Paper, prepublished online December 30, 2003

Submitted August 12, 2003

Accepted December 18, 2003

Reprogramming of human post-mitotic neutrophils into macrophages by

growth factors

Hiroto Araki, Naoyuki Katayama*, Yoshihiro Yamashita, Hiroyuki Mano,

Atsushi Fujieda, Eiji Usui, Hidetsugu Mitani, Kohshi Ohishi, Kazuhiro

Nishii, Masahiro Masuya, Nobuyuki Minami, Tsutomu Nobori, and Hiroshi

Shiku

The Second Department of Internal Medicine, Mie University School of

Medicine, Tsu, Mie, Japan

Division of Functional Genomics, Jichi Medical School, Kawachi-gun,

Tochigi, Japan

Blood Transfusion Service, Mie University Hospital, Tsu, Mie, Japan

It is generally recognized that post-mitotic neutrophils give rise to

polymorphonuclear neutrophils alone. We obtained evidence for a

lineage switch of human post-mitotic neutrophils into macrophages in

culture.

When the CD15+CD14- cell population, which predominantly consists of

band neutrophils, was cultured with granulocyte/macrophage colony-

stimulating factor, tumor necrosis factor-, interferon-, and

interleukin-4, and subsequently with macrophage colony-stimulating

factor alone, the resulting cells had morphological, cytochemical,

and phenotypic features of macrophages; in contrast to the starting

population, they were negative for myeloperoxidase, specific

esterase, and lactoferrin and also upregulated non-specific esterase

activity and the expression of macrophage colony-stimulating factor

receptor, mannose receptor, and HLA-DR. CD15+CD14- cells proceeded to

macrophages through the CD15-CD14- cell population. Microarray

analysis of gene expression also disclosed the lineage conversion

from neutrophils to macrophages.

Macrophages derived from CD15+CD14- neutrophils had phagocytic

function. Data obtained using three different techniques, including

Ki-67 staining, bromodeoxyuridine incorporation, and cytoplasmic dye

labeling, together with the yield of cells, indicated that the

generation of macrophages from CD15+CD14- neutrophils did not result

from a contamination of progenitors for macrophages.

Our data show that in response to cytokines, post-mitotic neutrophils

can become macrophages. This may represent another differentiation

pathway toward macrophages in human postnatal hematopoiesis.