title: Neu1 sialidase and matrix metalloproteinase-9 cross-talk regulates nucleic acid-induced endosomal TOLL-like receptor-7 and -9 activation, cellular signaling and pro-inflammatory responses.
abstract: 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-κB (NF-κB-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-κB activation and proinflammatory TNFα 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-κB activation and pro-inflammatory responses.
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada. samarma@hotmail.com
authors.forename: Samar
authors.initials: S
authors.lastname: Abdulkhalek
authors.forename: Myron R
authors.initials: MR
authors.lastname: Szewczuk
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D000077271:Imiquimod; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007369:Interferon Inducers / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology; D053139:Oseltamivir / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D007369:Interferon Inducers; D016328:NF-kappa B; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D018004:Receptors, Bombesin; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D053139:Oseltamivir; C110128:Neu1 protein, mouse; D009439:Neuraminidase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000077271:Imiquimod
keywords: 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid; 4MUNANA; 50% inhibitory concentration; G-protein coupled receptor; GPCR; GPCR Gα proteins; GPCR signaling; IC(50); MMP; MMP9; Macrophage cells; NMBR receptors; Neu1 sialidase; SEAP; TLR; TLR signaling; TOLL-like receptors; Tamiflu; matrix metalloproteinase; oseltamivir phosphate; secreted embryonic alkaline phosphatase