Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants
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 signal...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | http://www.mdpi.com/1422-0067/18/3/595 |
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| author | Louise Tzung-Harn Hsieh Madalina-Viviana Nastase Heiko Roedig Jinyang Zeng-Brouwers Chiara Poluzzi Stephanie Schwalm Christian Fork Claudia Tredup Ralf P. Brandes Malgorzata Wygrecka Andrea Huwiler Josef Pfeilschifter Liliana Schaefer |
| author_facet | Louise Tzung-Harn Hsieh Madalina-Viviana Nastase Heiko Roedig Jinyang Zeng-Brouwers Chiara Poluzzi Stephanie Schwalm Christian Fork Claudia Tredup Ralf P. Brandes Malgorzata Wygrecka Andrea Huwiler Josef Pfeilschifter Liliana Schaefer |
| author_sort | Louise Tzung-Harn Hsieh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:19:39Z |
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| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T12:19:39Z |
| publishDate | 2017-03-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2a6d7d4ef66c43ffbc7e3fe20df9312b2022-12-22T03:33:19ZengMDPI AGInternational Journal of Molecular Sciences1422-00672017-03-0118359510.3390/ijms18030595ijms18030595Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage ChemoattractantsLouise Tzung-Harn Hsieh0Madalina-Viviana Nastase1Heiko Roedig2Jinyang Zeng-Brouwers3Chiara Poluzzi4Stephanie Schwalm5Christian Fork6Claudia Tredup7Ralf P. Brandes8Malgorzata Wygrecka9Andrea Huwiler10Josef Pfeilschifter11Liliana Schaefer12Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyInstitut für Kardiovaskulare Physiologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyInstitut für Kardiovaskulare Physiologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyDepartment of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, Giessen 35392, GermanyInstitute of Pharmacology, University of Bern, Inselspital INO-F, Bern CH-3010, SwitzerlandPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyPharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, GermanyIn 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.http://www.mdpi.com/1422-0067/18/3/595damage-associated molecular patternsmall leucine-rich proteoglycantoll-like receptorschemoattractantextracellular matrixlipid signalingsphingolipidmacrophage |
| spellingShingle | Louise Tzung-Harn Hsieh Madalina-Viviana Nastase Heiko Roedig Jinyang Zeng-Brouwers Chiara Poluzzi Stephanie Schwalm Christian Fork Claudia Tredup Ralf P. Brandes Malgorzata Wygrecka Andrea Huwiler Josef Pfeilschifter Liliana Schaefer Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants International Journal of Molecular Sciences damage-associated molecular pattern small leucine-rich proteoglycan toll-like receptors chemoattractant extracellular matrix lipid signaling sphingolipid macrophage |
| title | Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants |
| title_full | Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants |
| title_fullStr | Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants |
| title_full_unstemmed | Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants |
| title_short | Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants |
| title_sort | biglycan and sphingosine kinase 1 signaling crosstalk regulates the synthesis of macrophage chemoattractants |
| topic | damage-associated molecular pattern small leucine-rich proteoglycan toll-like receptors chemoattractant extracellular matrix lipid signaling sphingolipid macrophage |
| url | http://www.mdpi.com/1422-0067/18/3/595 |
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