Louise Tzung-Harn Hsieh, Mădălina-Viviana Năstase, Heiko Rödig, Jinyang Zeng-Brouwers, Chiara Poluzzi, Stephanie Schwalm, Christian Fork, Claudia Tredup, Ralf Brandes, Malgorzata Wygrecka, Andrea Huwiler, Josef Pfeilschifter, Liliana Schäfer
- 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.
MetadatenAuthor: | Louise Tzung-Harn Hsieh, Mădălina-Viviana NăstaseGND, Heiko RödigGND, Jinyang Zeng-Brouwers, Chiara Poluzzi, Stephanie SchwalmGND, Christian Fork, Claudia Tredup, Ralf BrandesORCiDGND, Malgorzata Wygrecka, Andrea HuwilerORCiDGND, Josef PfeilschifterGND, Liliana SchäferORCiD |
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URN: | urn:nbn:de:hebis:30:3-440646 |
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DOI: | https://doi.org/10.3390/ijms18030595 |
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ISSN: | 1422-0067 |
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ISSN: | 1661-6596 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/28282921 |
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Parent Title (English): | International journal of molecular sciences |
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Publisher: | Molecular Diversity Preservation International |
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Place of publication: | Basel |
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Contributor(s): | Cheorl-Ho Kim |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2017/04/25 |
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Date of first Publication: | 2017/03/09 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/04/25 |
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Tag: | chemoattractant; damage-associated molecular pattern; extracellular matrix; lipid signaling; macrophage; small leucine-rich proteoglycan; sphingolipid; toll-like receptors |
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Volume: | 18 |
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Issue: | 3, Art. 595 |
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Page Number: | 18 |
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First Page: | 1 |
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Last Page: | 18 |
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Note: | © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
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HeBIS-PPN: | 421370181 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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