G-CSF-induced sympathetic tone provokes fever and primes antimobilizing functions of neutrophils via PGE2

Abstract

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 E (PGE) from hematopoietic cells modulated the bone marrow (BM) microenvironment. Neutrophils from steady-state BM constitutively expressed mPGES-1 and significantly enhanced PGE 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 PGE synthesis from exogenous deuterium-labeled AA. Spontaneous PGE production was highly efficient in Gr-1 neutrophils among BM cells from G-CSF-treated mice. In addition to these in vitro data, the in vivo depletion of Gr-1 neutrophils disrupted G-CSF-induced fever. Furthermore, sympathetic denervation eliminated both neutrophil priming for PGE production and fever during G-CSF treatment. Thus, sympathetic tone-primed BM neutrophils were identified as one of the major PGE producers. PGE upregulated osteopontin, specifically in preosteoblasts, to retain progenitors in the BM via EP4 receptor. Thus, the sympathetic nervous system regulated neutrophils as an indispensable PGE 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.

Neutrophils as effectors of vascular inflammation

“…Surprisingly, studies in murine models of myocardial injury have shown that adrenergic signalling directly on leucocytes modulates inflammation. Although different forms of β‐adrenergic receptors are expressed on neutrophils, β1‐AR was found to be critical in early stages of myocardial injury: an antagonist for this receptor impaired the migration of neutrophils towards chemotactic stimuli in vitro and hematopoietic‐specific deficiency in the receptor protected from acute injury during the early stages of infarction . Interestingly, inhibition of this receptor leads to aberrant morphology of intravascular neutrophils and reduced motility, similar to that found upon disruption of platelet‐neutrophil interactions .…”

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

“…At end-product of the arachidonic acid pathway, PGE2 can reportedly expand HSCs in vitro and in vivo [45,46]. Moreover, neutrophil-derived PGE2 inhibits G-CSF-mediated HSPC mobilization [47]. These observations indicate that the relationship of FA-derived lipid molecules to HSC dynamics should be further investigated.…”

The complexity of neutrophils in health and disease: Focus on cancer

“…In particular, a subset of granulocytes expressing the histidine-decarboxylase and histamine was shown to support the quiescence of myeloid-biased HSCs [ 117 ]. Moreover, BM neutrophils can secrete prostaglandin E 2 which promotes the retention of HSC in the BM through the production of osteopontin by the preosteoblasts [ 118 ].…”