title: Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants.
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.
authors.affiliation: Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. hsiehlouise@gmail.com.
authors.forename: Louise Tzung-Harn
authors.initials: LT
authors.lastname: Hsieh
authors.affiliation: 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.|National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Avenue, Bucharest 031299, Romania. madalina.nastase@gmail.com.
authors.forename: Madalina-Viviana
authors.initials: MV
authors.lastname: Nastase
authors.affiliation: 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.
authors.forename: Heiko
authors.initials: H
authors.lastname: Roedig
authors.affiliation: Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. jinyangzeng@web.de.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Zeng-Brouwers
authors.affiliation: Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. chiarapoluzzi@yahoo.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Poluzzi
authors.affiliation: 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.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schwalm
authors.affiliation: Institut für Kardiovaskulare Physiologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. fork@vrc.uni-frankfurt.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Fork
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tredup
authors.affiliation: Institut für Kardiovaskulare Physiologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany. brandes@vrc.uni-frankfurt.de.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: 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.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.affiliation: Institute of Pharmacology, University of Bern, Inselspital INO-F, Bern CH-3010, Switzerland. huwiler@pki.unibe.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
authors.affiliation: 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.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.affiliation: 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.
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D058578:Biglycan / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D058578:Biglycan; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017853:Phosphotransferases (Alcohol Group Acceptor); D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse
keywords: chemoattractant; damage-associated molecular pattern; extracellular matrix; lipid signaling; macrophage; small leucine-rich proteoglycan; sphingolipid; toll-like receptors