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Int J Mol Sci. 2017 Mar 9;18(3). pii: E595. doi: 10.3390/ijms18030595.

Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants.

Author information

1
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. hsiehlouise@gmail.com.
2
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. madalina.nastase@gmail.com.
3
National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Avenue, Bucharest 031299, Romania. madalina.nastase@gmail.com.
4
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. heiko.roedig@live.de.
5
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. jinyangzeng@web.de.
6
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. chiarapoluzzi@yahoo.it.
7
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. s.schwalm@med.uni-frankfurt.de.
8
Institut für Kardiovaskulare Physiologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. fork@vrc.uni-frankfurt.de.
9
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. tredup@em.uni-frankfurt.de.
10
Institut für Kardiovaskulare Physiologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. brandes@vrc.uni-frankfurt.de.
11
Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, Giessen 35392, Germany. malgorzata.wygrecka@innere.med.uni-giessen.de.
12
Institute of Pharmacology, University of Bern, Inselspital INO-F, Bern CH-3010, Switzerland. huwiler@pki.unibe.ch.
13
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. pfeilschifter@em.uni-frankfurt.de.
14
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. schaefer@med.uni-frankfurt.de.

Abstract

In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 through selective utilization of Toll-like receptors (TLRs) and their adaptor molecules. However, the respective downstream signaling events resulting in biglycan-induced CCL2 and CCL5 production have not yet been defined. Here, we show that biglycan stimulates the production and activation of sphingosine kinase 1 (SphK1) in a TLR4- and Toll/interleukin (IL)-1R domain-containing adaptor inducing interferon (IFN)-β (TRIF)-dependent manner in murine primary macrophages. We provide genetic and pharmacological proof that SphK1 is a crucial downstream mediator of biglycan-triggered CCL2 and CCL5 mRNA and protein expression. This is selectively driven by biglycan/SphK1-dependent phosphorylation of the nuclear factor NF-κB p65 subunit, extracellular signal-regulated kinase (Erk)1/2 and p38 mitogen-activated protein kinases. Importantly, in vivo overexpression of soluble biglycan causes Sphk1-dependent enhancement of renal CCL2 and CCL5 and macrophage recruitment into the kidney. Our findings describe the crosstalk between biglycan- and SphK1-driven extracellular matrix- and lipid-signaling. Thus, SphK1 may represent a new target for therapeutic intervention in biglycan-evoked inflammatory conditions.

KEYWORDS:

chemoattractant; damage-associated molecular pattern; extracellular matrix; lipid signaling; macrophage; small leucine-rich proteoglycan; sphingolipid; toll-like receptors

PMID:
28282921
PMCID:
PMC5372611
DOI:
10.3390/ijms18030595
[Indexed for MEDLINE]
Free PMC Article

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