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Int. J. Mol. Sci. 2017, 18(3), 595; doi:10.3390/ijms18030595

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

1
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
2
Institut für Kardiovaskulare Physiologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
3
Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, Giessen 35392, Germany
4
Institute of Pharmacology, University of Bern, Inselspital INO-F, Bern CH-3010, Switzerland
5
National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Avenue, Bucharest 031299, Romania
*
Author to whom correspondence should be addressed.
Academic Editor: Cheorl-Ho Kim
Received: 14 February 2017 / Revised: 27 February 2017 / Accepted: 6 March 2017 / Published: 9 March 2017
(This article belongs to the Special Issue Pain and Inflammation)
View Full-Text   |   Download PDF [2697 KB, uploaded 9 March 2017]   |  

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. View Full-Text
Keywords: damage-associated molecular pattern; small leucine-rich proteoglycan; toll-like receptors; chemoattractant; extracellular matrix; lipid signaling; sphingolipid; macrophage damage-associated molecular pattern; small leucine-rich proteoglycan; toll-like receptors; chemoattractant; extracellular matrix; lipid signaling; sphingolipid; macrophage
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Hsieh, L.T.-H.; Nastase, M.-V.; Roedig, H.; Zeng-Brouwers, J.; Poluzzi, C.; Schwalm, S.; Fork, C.; Tredup, C.; Brandes, R.P.; Wygrecka, M.; Huwiler, A.; Pfeilschifter, J.; Schaefer, L. Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants. Int. J. Mol. Sci. 2017, 18, 595.

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