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Topical treatment targeting sphingosine-1-phosphate and sphingosine lyase abrogates experimental allergic rhinitis in a murine model

A KleinJan, M van Nimwegen, K Leman, HC Hoogsteden and Bart Lambrecht UGent (2013) ALLERGY. 68(2). p.204-212
abstract
Background Sphingosine-1-phosphate (S1P) plays a crucial role in homeostasis of the immune system by regulating lymphocyte recirculation and inflammatory cell recruitment. The levels of S1P are tightly controlled through regulated production and controlled breakdown by sphingosine-lyase (SL). The S1P analogue FTY720 has been developed as an immunosuppressant in transplantation and tested as a treatment for various inflammatory diseases. FTY720 exploits S1P biology by acting as a S1P1 and S1P 3 agonist and by inhibiting S1P breakdown by SL. Objective Here, we investigate interfering S1P in allergic rhinitis (AR) and its way of action. Methods Allergic rhinitis was induced by sensitizing mice to ovalbumin (OVA) and challenging the nose with OVA allergen. At the time of allergen challenge, mice received topical intranasal treatment with FTY720. To address the relative contribution of SL inhibition in mediating its effects, some mice were treated with the SL inhibitor 2-acetyl-4-tetrahydroxybutyl (THI). Results FTY720 treatment resulted in significantly fewer eosinophils, mast cells and dendritic cells in the nasal mucosa of AR animals, compared with diluent treatment. Levels of IL-4, IL-5, IL-10 and IL-13 produced by lymph node cells fell significantly in FTY720-treated animals. Moreover, FTY720 proved potent enough to suppress inflammation in a model of persistent AR. In vitro and in vivo experiments indicate that FTY720 impaired Th2 differentiation and proliferation important in driving eosinophilia and induced apoptosis in mast cells. Conclusion Our results indicate that interfering with S1P metabolism is a powerful and feasible strategy to develop new topical agents that suppress AR.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
sphingosine lyase, eosinophils, dendritic cell, allergic rhinitis, T-CELLS, DENDRITIC CELLS, NASAL-MUCOSA, MAST-CELLS, FTY720, ASTHMA, RECEPTOR, INHIBITION, KINASE, MICE, sphingosine-1-P
journal title
ALLERGY
Allergy
volume
68
issue
2
pages
204 - 212
Web of Science type
Article
Web of Science id
000313727300009
JCR category
ALLERGY
JCR impact factor
5.995 (2013)
JCR rank
2/21 (2013)
JCR quartile
1 (2013)
ISSN
0105-4538
DOI
10.1111/all.12082
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3156105
handle
http://hdl.handle.net/1854/LU-3156105
date created
2013-03-04 17:09:15
date last changed
2016-12-19 15:46:46
@article{3156105,
  abstract     = {Background Sphingosine-1-phosphate (S1P) plays a crucial role in homeostasis of the immune system by regulating lymphocyte recirculation and inflammatory cell recruitment. The levels of S1P are tightly controlled through regulated production and controlled breakdown by sphingosine-lyase (SL). The S1P analogue FTY720 has been developed as an immunosuppressant in transplantation and tested as a treatment for various inflammatory diseases. FTY720 exploits S1P biology by acting as a S1P1 and S1P 3 agonist and by inhibiting S1P breakdown by SL. Objective Here, we investigate interfering S1P in allergic rhinitis (AR) and its way of action. Methods Allergic rhinitis was induced by sensitizing mice to ovalbumin (OVA) and challenging the nose with OVA allergen. At the time of allergen challenge, mice received topical intranasal treatment with FTY720. To address the relative contribution of SL inhibition in mediating its effects, some mice were treated with the SL inhibitor 2-acetyl-4-tetrahydroxybutyl (THI). Results FTY720 treatment resulted in significantly fewer eosinophils, mast cells and dendritic cells in the nasal mucosa of AR animals, compared with diluent treatment. Levels of IL-4, IL-5, IL-10 and IL-13 produced by lymph node cells fell significantly in FTY720-treated animals. Moreover, FTY720 proved potent enough to suppress inflammation in a model of persistent AR. In vitro and in vivo experiments indicate that FTY720 impaired Th2 differentiation and proliferation important in driving eosinophilia and induced apoptosis in mast cells. Conclusion Our results indicate that interfering with S1P metabolism is a powerful and feasible strategy to develop new topical agents that suppress AR.},
  author       = {KleinJan, A and van Nimwegen, M and Leman, K and Hoogsteden, HC and Lambrecht, Bart},
  issn         = {0105-4538},
  journal      = {ALLERGY},
  keyword      = {sphingosine lyase,eosinophils,dendritic cell,allergic rhinitis,T-CELLS,DENDRITIC CELLS,NASAL-MUCOSA,MAST-CELLS,FTY720,ASTHMA,RECEPTOR,INHIBITION,KINASE,MICE,sphingosine-1-P},
  language     = {eng},
  number       = {2},
  pages        = {204--212},
  title        = {Topical treatment targeting sphingosine-1-phosphate and sphingosine lyase abrogates experimental allergic rhinitis in a murine model},
  url          = {http://dx.doi.org/10.1111/all.12082},
  volume       = {68},
  year         = {2013},
}

Chicago
KleinJan, A, M van Nimwegen, K Leman, HC Hoogsteden, and Bart Lambrecht. 2013. “Topical Treatment Targeting Sphingosine-1-phosphate and Sphingosine Lyase Abrogates Experimental Allergic Rhinitis in a Murine Model.” Allergy 68 (2): 204–212.
APA
KleinJan, A, van Nimwegen, M., Leman, K., Hoogsteden, H., & Lambrecht, B. (2013). Topical treatment targeting sphingosine-1-phosphate and sphingosine lyase abrogates experimental allergic rhinitis in a murine model. ALLERGY, 68(2), 204–212.
Vancouver
1.
KleinJan A, van Nimwegen M, Leman K, Hoogsteden H, Lambrecht B. Topical treatment targeting sphingosine-1-phosphate and sphingosine lyase abrogates experimental allergic rhinitis in a murine model. ALLERGY. 2013;68(2):204–12.
MLA
KleinJan, A, M van Nimwegen, K Leman, et al. “Topical Treatment Targeting Sphingosine-1-phosphate and Sphingosine Lyase Abrogates Experimental Allergic Rhinitis in a Murine Model.” ALLERGY 68.2 (2013): 204–212. Print.