Granulocyte colony-stimulating factor (
G-CSF) is widely used for peripheral blood stem/progenitor mobilization.
G-CSF causes low-grade
fever that is ameliorated by nonsteroidal anti-inflammatory drugs (
NSAIDs), suggesting the activation of
arachidonic acid (AA) cascade. How
G-CSF regulated this reaction was assessed.
G-CSF treatment in mice resulted in
fever, which was canceled in
prostaglandin E synthase (mPGES-1)-deficient mice. Mobilization efficiency was twice as high in chimeric mice lacking mPGES-1, specifically in hematopoietic cells, suggesting that
prostaglandin E2 (
PGE2) from hematopoietic cells modulated the bone marrow (BM) microenvironment. Neutrophils from steady-state BM constitutively expressed mPGES-1 and significantly enhanced
PGE2 production in vitro by β-
adrenergic stimulation, but not by
G-CSF, which was inhibited by an
NSAID. Although neutrophils expressed all β-
adrenergic receptors, only β3-agonist induced this phenomenon. Liquid chromatography-tandem mass spectrometry traced β-agonist-induced
PGE2 synthesis from exogenous
deuterium-labeled AA. Spontaneous
PGE2 production was highly efficient in Gr-1high neutrophils among BM cells from
G-CSF-treated mice. In addition to these in vitro data, the in vivo depletion of Gr-1high neutrophils disrupted
G-CSF-induced
fever. Furthermore,
sympathetic denervation eliminated both neutrophil priming for
PGE2 production and
fever during
G-CSF treatment. Thus, sympathetic tone-primed BM neutrophils were identified as one of the major
PGE2 producers.
PGE2 upregulated
osteopontin, specifically in preosteoblasts, to retain progenitors in the BM via EP4 receptor. Thus, the sympathetic nervous system regulated neutrophils as an indispensable
PGE2 source to modulate BM microenvironment and body temperature. This study provided a novel mechanistic insight into the communication of the nervous system, BM niche components, and hematopoietic cells.