Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants
AbstractIn 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
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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.
Hsieh LT-H, Nastase M-V, Roedig H, Zeng-Brouwers J, Poluzzi C, Schwalm S, Fork C, Tredup C, Brandes RP, Wygrecka M, Huwiler A, Pfeilschifter J, Schaefer L. Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants. International Journal of Molecular Sciences. 2017; 18(3):595.Chicago/Turabian Style
Hsieh, Louise T.-H.; Nastase, Madalina-Viviana; Roedig, Heiko; Zeng-Brouwers, Jinyang; Poluzzi, Chiara; Schwalm, Stephanie; Fork, Christian; Tredup, Claudia; Brandes, Ralf P.; Wygrecka, Malgorzata; Huwiler, Andrea; Pfeilschifter, Josef; Schaefer, Liliana. 2017. "Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants." Int. J. Mol. Sci. 18, no. 3: 595.
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