Journal
CELLULAR SIGNALLING
Volume 25, Issue 11, Pages 2093-2105Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.06.010
Keywords
Neu1 sialidase; GPCR G alpha proteins; MMP9; Macrophage cells; TLR signaling; NMBR receptors; GPCR signaling
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- R.S. McLaughlin Scholarship
- Ontario Graduate Scholarship
- Canadian Institutes of Health Research (CIHR) Doctoral Award
- Frederick Banting Graduate Scholarship
- Charles Best Canada Graduate Scholarship
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The precise mechanism(s) by which intracellular TOLL-like receptors (TLRs) become activated by their ligands remains unclear. Here, we report a molecular organizational G-protein coupled receptor (GPCR) signaling platform to potentiate a novel mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B GPCR, all of which form a tripartite complex with TLR-7 and -9. siRNA silencing Neu1, MMP-9 and neuromedin-B GPCR in RAW-blue macrophage cells significantly reduced TLR7 imiquimod- and TLR9 ODN1826-induced NF-kappa B (NF-kappa B-pSer(536)) activity. Tamiflu, specific MMP-9 inhibitor, neuromedin B receptor specific antagonist BIM23127, and the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 significantly block nucleic acid-induced TLR-7 and -9 MyD88 recruitment, NF-kappa B activation and proinflammatory TNF alpha and MCP-1 cytokine responses. For the first time, Neu1 clearly plays a central role in mediating nucleic acid-induced intracellular TLR activation, and the interactions involving NMBR-MMP9-Neu1 cross-talk constitute a novel intracellular TLR signaling platform that is essential for NF-kappa B activation and pro-inflammatory responses. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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