G-CSF-induced sympathetic tone provokes fever and primes antimobilizing functions of neutrophils via PGE2.
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 PGE2production 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 PGE2synthesis from exogenous deuterium-labeled AA. Spontaneous PGE2production was highly efficient in Gr-1highneutrophils among BM cells from G-CSF-treated mice. In addition to these in vitro data, the in vivo depletion of Gr-1highneutrophils disrupted G-CSF-induced fever. Furthermore, sympathetic denervation eliminated both neutrophil priming for PGE2production and fever during G-CSF treatment. Thus, sympathetic tone-primed BM neutrophils were identified as one of the major PGE2producers. PGE2upregulated osteopontin, specifically in preosteoblasts, to retain progenitors in the BM via EP4 receptor. Thus, the sympathetic nervous system regulated neutrophils as an indispensable PGE2source 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.
Hematology, Department of Medicine.
Yuko
Y
Kawano
Hematology, Department of Medicine.
Chie
C
Fukui
The Integrated Center for Mass Spectrometry, and.|Department of Community Medicine and Social Health Care, Division of Epidemiology, Kobe University Graduate School of Medicine, Kobe, Japan.
Masakazu
M
Shinohara
Hematology, Department of Medicine.
Kanako
K
Wakahashi
Hematology, Department of Medicine.
Shinichi
S
Ishii
Hematology, Department of Medicine.
Tomohide
T
Suzuki
Hematology, Department of Medicine.|Department of Oral Biochemistry and Molecular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
Mari
M
Sato
Hematology, Department of Medicine.
Noboru
N
Asada
Hematology, Department of Medicine.
Hiroki
H
Kawano
Hematology, Department of Medicine.
Kentaro
K
Minagawa
Hematology, Department of Medicine.
Akiko
A
Sada
Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe, Japan.
Tomoyuki
T
Furuyashiki
Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba, Japan.|Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Satoshi
S
Uematsu
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.|Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Shizuo
S
Akira
Department of Matrix Medicine, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Toshimitsu
T
Uede
Department of Drug Discovery Medicine and Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; and.
Shuh
S
Narumiya
Department of Hematology, Nishiwaki Municipal Hospital, Nishiwaki, Japan.
Toshimitsu
T
Matsui
Hematology, Department of Medicine.
Yoshio
Y
Katayama
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism*; D005334:Fever / Q000139:chemically induced* / Q000235:genetics; D017353:Gene Deletion; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D016179:Granulocyte Colony-Stimulating Factor; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone