Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, Wang J. Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system. Brain Behav Immun. 2015 Jan;43:172-83

Abstract The sympathetic nervous system plays critical roles in the differentiation, maturation and recruitment of immune cells under homeostatic conditions, and in responses to environmental stimuli, although its role in the migratory control of immune cells during acute inflammation remains unclear. In this study, using an advanced intravital bone imaging system established in our laboratory, we demonstrated that the sympathetic nervous system locally regulates neutrophil egress from the bone marrow for mobilization to inflammatory foci. We found that sympathetic neurons were located close to blood vessels in the bone marrow cavity; moreover, upon lipopolysaccharide (LPS) administration, local sympathectomy delayed neutrophil egress from the bone marrow and increased the proportion of neutrophils that remained in place. We also showed that vascular endothelial cells produced C-X-C motif chemokine ligand 1 (CXCL1), which is responsible for neutrophil egress out of the bone marrow. Its expression was up-regulated during acute inflammation, and was suppressed by β-adrenergic receptor blockade, which was accompanied with inhibition of neutrophil egress into the systemic circulation. Furthermore, systemic β-adrenergic signaling blockade decreased the recruitment of neutrophils in the lung under conditions of acute systemic inflammation. Taken together, the results of this study first suggested a new regulatory system, wherein local sympathetic nervous activation promoted neutrophil egress by enhancing Cxcl1 expression in bone marrow endothelial cells in a β-adrenergic signaling-dependent manner, contributing to the recruitment of neutrophils at the onset of inflammation in vivo.

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Signals from the Sympathetic Nervous System Regulate Hematopoietic Stem Cell Egress from Bone Marrow

Cell ◽

10.1016/j.cell.2005.10.041 ◽

2006 ◽

Vol 124 (2) ◽

pp. 407-421 ◽

Cited By ~ 861

Author(s):

Yoshio Katayama ◽

Michela Battista ◽

Wei-Ming Kao ◽

Andrés Hidalgo ◽

Anna J. Peired ◽

...

Keyword(s):

Bone Marrow ◽

Nervous System ◽

Stem Cell ◽

Sympathetic Nervous System ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem ◽

Sympathetic Nervous

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Granulocyte Colony-Stimulating Factor (G-CSF) Stimulates Sympathetic Nervous System Activity in the Bone Marrow

Blood ◽

10.1182/blood.v112.11.2419.2419 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2419-2419 ◽

Cited By ~ 1

Author(s):

Michela Battista ◽

Simon Mendez-Ferrer ◽

Paul S. Frenette

Keyword(s):

Bone Marrow ◽

Nervous System ◽

Plasma Membrane ◽

Sympathetic Nervous System ◽

Lipid Rafts ◽

Synaptic Cleft ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Sympathetic Nervous ◽

Stimulating Factor

Abstract Granulocyte colony-stimulating factor (G-CSF) is the agent most commonly used clinically to elicit hematopoietic stem and progenitor cells (HSPCs) mobilization from the bone marrow (BM) to the peripheral blood. Our previous studies indicate the sympathetic nervous system (SNS) controls G-CSF-induced HSPCs egress from the BM and that G-CSF decreases catecholamine levels in bone/BM tissues (Cell2006; 124:407). However the molecular basis for this depletion is unknown. Here we show that G-CSF stimulates selectively the activity of the SNS in bone/BM microenvironment in mice. Norepinephrine (NE), a catecholamine and the principal neurotransmitter of the SNS, is synthesized by the rate-limiting enzyme tyrosine hydroxylase (TH). Since TH is a catecholaminergic marker which reflects the extent of sympathetic innervation, we evaluated its expression in bone/BM tissues after G-CSF treatment. TH immunofluorescence staining analysis in longitudinal frozen sections of femurs exhibited a strong punctuate staining of the catecholamine-producing enzyme that was increased 10-fold in G-CSF-treated mice compared to control animals. This result was also confirmed by Western blot analysis of equal amount of protein obtained from BM lysates of G-CSF-treated and control animals. Because NE release and removal from the extracellular space determine tissue NE turnover and regulate the sympathetic activation, we evaluated NE release and uptake in sympathetic cervical ganglia (SCG) in organ cultures treated with G-CSF. Although the release of [3H]NE from cultured ganglia was not affected by G-CSF, we found a significant reduction in the reuptake rate. NE clearance from the synaptic cleft is mediated by the Na+-dependent NE transporter (NET). NET is selectively expressed and localized in lipid rafts of the plasma membrane of the noradrenergic nerve terminals and it is internalized as a result of its down-regulation. We thus isolated lipid rafts from BM homogenized in lysis buffer containing 1% Triton X-100 and subjected to sucrose gradient centrifugation. We found that G-CSF induced the redistribution of NET from the plasma membrane as revealed by a strong reduction of NET levels in BM lipid raft-enriched gradient fractions and by an increase of NET levels in BM non-raft fractions following G-CSF treatment. Moreover Q-PCR analysis of catecholamine-inactivating enzymes revealed reduced mRNA levels of the monoamine oxidase (MAO) and the catechol-O-methyltransferase (COMT) enzymes derived from BM of mice injected with G-CSF compared to untreated animals. Altogether, these results demonstrate that G-CSF treatment affects NE turnover impairing the removal of NE from the synaptic cleft and therefore leading to an increase of the concentration of the extracellular NE. A likely consequence is a prolongation of the postsynaptic action of NE on its receptors and ultimately an augmented sympathetic activity in the bone marrow microenvironment.

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