Neuropeptide control of bone marrow neutrophil production is mediated by both direct and indirect effects on CFU-GM (original) (raw)
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Neuropeptide Control of Bone Marrow Neutrophil Production: A Key Axis for Neuroimmunomodulation
Annals of the New York Academy of Sciences, 2006
A BSTRACT : Nerve fibers project into the bone marrow and terminate in association with stromal cells. Nerve terminals are also associated with antigenprocessing and-presenting cells throughout the body and have been shown to be important in leukocyte trafficking and wound healing as well as hemopoiesis. Here we show that neuropeptide input to the bone marrow is vital to normal granulopoiesis and that deletion of the neuropeptides, substance P, and calcitonin gene-related peptide (CGRP), with the neurotoxin, capsaicin, abrogates normal blood cell production. Norepinephrine, neurokinins a and 2, and vasoactive intestinal peptide all have inhibitory effects on in vitro CFU-GM colony formation. Substance P, neurokinin 1, nerve growth factor, and CGRP have stimulatory effects on CFU-GM. Furthermore, in vitro experiments show that, apart from CGRP, all the neuroactive substances we tested operate through effects on accessory cells, stimulating the release of regulatory molecules that have a direct effect on purified CFU-GM.
Neuroscience Letters, 2006
Bone marrow is richly innervated with both myelinated and non-myelinated nerve fibers, but the role of this innervation on hemopoiesis is poorly understood. Therefore, the aim of this study was to investigate the role of C-fibers on hematopoiesis. Wistar rats were neonatally injected with either capsaicin or its vehicle, and used at adult ages (8-10 weeks). In capsaicin-pretreated rats, the levels of substance P (SP) in bone marrow fluid were markedly reduced in comparison with the vehicle group (13.1 ± 4.5 pg/ml versus 47.3 ± 5.5 pg/ml, p < 0.05). In bone marrow, the number of total leukocytes was 28% higher (p < 0.05) in capsaicin-pretreated group, and this accompanied by a higher number of neutrophils, particularly of the immature forms. The mononuclear cell and eosinophils counts did not differ significantly among vehicle and capsaicin groups. In peripheral blood, the number of circulating neutrophils in the capsaicin group increased by 53.8% (p < 0.05), whereas the number of mononuclear cells did not change significantly among groups. Eosinophils were virtually absent in the circulating blood in both groups. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) showed that both preprotachykinin (PPT)-I mRNA and the tachykinin neurokinin (NK)-1 mRNA expression in bone marrow cells significantly increased in capsaicin group, whereas the NK-2 mRNA expression was unchanged after capsaicin pretreatment. In conclusion, our data show that chronic neuropeptide depletion enhance the neutrophil proliferation and differentiation in the rat bone marrow by mechanisms involving upregulation of PPT-I gene and NK-1 receptors.
Neurokinin receptors: relevance to the emerging immune system
Archivum immunologiae et therapiae experimentalis
The adult bone marrow (BM )is the major site of the emerging immune system. Hematopoiesis is the process whereby immune cells are generated from a finite number of hematopoietic stem cells. Hematopoiesis is regulated by soluble mediators and inter cellular interactions. A major regulatory mechanism of hematopoiesis involves bidirectional crosstalk with the neural system. This communication mainly occurs by the release of neurotransmitters from innervated fibers. The neurotransmitters interact with specific receptors on BM resident cells and release other hematopoietic regulators such as cytokines. Together, the neurotransmitters and cytokines form a complex network to regulate hematopoiesis. Among BM resident cells, the stromal cells are particularly relevant for two reasons:1) they represent non-neural sources of neurotransmitters, and 2) stromal cells express specific receptors for neurotransmitters. This review focuses on the hematopoietic effects of neurotransmitters belonging t...
Neuropeptides, 2010
Background: Modulation of the expression of CXCR4 as a critical adhesion molecule on cord blood (CB) CD34 + cells could overcome delay following cord blood transplantation. Identification of beneficial effects of growth factors including cytokines and neuropeptides on CXCR4 expression would enable our understanding of this complicated network. Therefore, we aimed to assess the role of substance P (SP) and Calcitonin gene related peptide (CGRP) on CXCR4 levels. Material and methods: CD34 + cells purified from CB were cultured in a serum-free liquid culture system. Different concentrations of SP and CGRP were used in combination with cytokine cocktail. Expression of CXCR4 at protein and genomic levels was assessed by flow cytometry and real time RT-PCR. Results: Our results indicate increased CXCR4 + CD34 + cells after 7 days cultivation with SP and/or CGRP. Increased gene expression of the CXCR4 molecule was observed at 10 À9 M either SP or CGRP individually, by day 11 as compared to control group. Conclusions: Our study indicates that SP and CGRP induce CXCR4 protein expression in short term culture, and stimulate its expression. Consequently, the increased expression of CXCR4 could improve engraftment of CB CD34 + cells.
Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma
Blood, 1996
The tachykinins are a family of neuropeptides that share a common carboxyl terminus. Substance P (SP) and neurokinin-A (NK-A) are derived from the preprotachykinin l gene. Although SP and NK-A can bind to either NK-1, NK-2, or NK-3 receptors (R), they have preferences for NK- 1R and NK-2R, respectively. We have reported that SP stimulates erythroid (E) (burst-forming unit [BFU]-E and colony-forming unit [CFU]- E) and myeloid (CFU-granulocyte-macrophage [GM]) progenitors partly through the induction of growth factors. We have now investigated the hematopoietic effects of NK-A using short-term bone marrow (BM) cultures and found that NK-A (10(-7) to 10(-12) mol/L) inhibits CFU-GM proliferation but stimulates erythroid progenitors. Release of soluble factors by the stroma appears to mediate the inhibition because direct contact with the stroma was not required. We have found that NK-A, through NK-2-like receptors induces increased levels of macrophage inflammatory protein-1 alpha (MIP-...
POTENT ANTI-INFLAMMATORY ACTION OF CALCITONIN GENE-RELATED PEPTIDE
Calcitonin gene-related peptide (CGRP), but not substance P (SP), was found to inhibit edema-promoting actions of inflammatory mediators (histamine, leukotrine B4, 5-hydroxytryptamine) in vivo in the hamster cheek pouch, human skin, and rat paw. The effect of CGRP was present in the low nanomolar dose range, and it was mimicked by activation of sensory nerves with capsaicin which caused release of endogenous CGRP-like immunoreactivity (IR). The findings provide new information on the potential impact of sensory nerve activation during inflammatory processes by indicating that sensory nerves may play an anti-inflammatory role. The concept that neurotransmitters released from sensory nerves may cause "neurogenic inflammation" was introduced around the turn of the century, and the existence of this phenomenon is now based on several lines of experimental evidence (1). Among the neuropeptides suggested to mediate "neurogenic inflammation", attention has been paid particularly to SP and CGRP. Substance P causes both vasodilatation and plasma protein leakage (edema) in various tissues of different species (1), whereas CGRP is an exceedingly potent vasodilator with little or no ability to induce edema (1, 2). Accordingly, acute administration of capsaicin, known to activate C-type sensory nerves (1, 3), or antidromic nerve stimulation may cause release of SP and CGRP, and a microvascular response consisting of vasodilatation and plasma leakage in different tissues of certain laboratory animals (1, 3). Further in support of neuropeptides mediating inflammation, systemic pretreatment with capsaicin is suggested to reduce inflammation in response to antidromic nerve stimulation and certain pro-inflammatory stimuli by causing neuropeptide depletion and functional impairment of peripheral sensory neurons (1, 3). Yet, there are also observations indicating that the concept of sensory nerve activation as a pro-inflammatory mechanism may not be generally applicable. For example, although vasodilatation and increased local blood flow is a consistent reaction to antidromic nerve stimulation and acute challenge with capsaicin, inflammatory edema is often missing, especially in species higher that rodents, including man (3-7). In addition, there are reports that chemical or surgical sensory denervation may even enhance some types of experimental inflammatory responses (8-10). These discordant findings may reflect species or tissue-dependent differences in distribution and biological effects of SP and CGRP, or 1429
Tachykinins and neurokinin receptors in bone marrow functions: neural-hematopoietic link
Journal of Receptor, Ligand and Channel Research, 2010
After many decades of neuropeptide research, advances in the field of tachykinins have considerably increased and revealed their implications in several physiological processes. In this review we focus on the role of the tachykinins in the regulation of hematopoietic functions. Evidence has shown that neural control of this process is emerging as a significant category in hematopoietic modulation. In the context of this regulation, we discuss the existence of a complex network involving the neurokinin receptors, tachykinins and cytokines. This network is tightly regulated by each of its components. 52 Klassert et al Dovepress submit your manuscript | www.dovepress.com Dovepress
Shock, 2005
Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. CGRP failed to inhibit neutrophil recruitment induced by the direct chemoattractant platelet-activating factor, whereas it significantly inhibited LPSinduced KC generation, suggesting that the effect of CGRP on neutrophil recruitment is indirect, acting on chemokine production by resident cells. Pretreatment of mice with 1 mg of CGRP protects against a lethal dose of LPS. The CGRPinduced protection is receptor mediated because it is completely reverted by the CGRP receptor antagonist, CGRP 8-37. The protective effect of CGRP correlates with an inhibition of TNF-a and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-a released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.