title: CpG-oligodeoxynucleotide-induced TLR9 activation regulates macrophage TREM-1 expression and shedding.
abstract: CpG-oligonucleotide (ODN)-induced TLR9 activation exerts anti-inflammatory effects. TREM-1 is a DAP12-associated receptor, which is up-regulated in response to LPS-mediated TLR4 activation, and plays an essential role in innate immune response by augmenting the production of pro-inflammatory chemokines and cytokines. TREM-1 up-regulation resulted in a grave outcome in animal models, and in patients with sepsis and rheumatoid arthritis, while its soluble form (sTREM-1) exerted anti-inflammatory effects. We hypothesized that CpG-ODN regulates membrane TREM-1 expression and sTREM-1 shedding. The effect of CpG-ODN-induced TLR9 activation on TREM-1 expression and shedding was studied in mouse peritoneal macrophages and the mouse macrophage cell line RAW 264.7. While TREM-1 expression was not altered by CpG-ODN alone, stimulation with both LPS and CpG-ODN significantly abrogated TREM-1 LPS-induced up-regulation. Moreover, CpG-ODN-induced TLR9 activation either alone or in combination with LPS resulted in a significant increase of supernatant sTREM-1. The release of sTREM-1 was correlated positively with MMP-9 activity and was inhibited by chloroquine. These results suggest (i) a novel CpG-ODN-induced TLR9 pathway for the regulation of macrophage TREM-1 expression and MMP-9-mediated TREM-1 shedding; and (ii) a novel mechanism for an anti-inflammatory effect of CpG-ODN through abrogation of LPS-induced membrane TREM-1 up-regulation and increased MMP-9-mediated TREM-1 shedding.
authors.affiliation: 1Laboratory of Inflammation Research, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Molad
authors.forename: Elisheva
authors.initials: E
authors.lastname: Pokroy-Shapira
authors.forename: Vered
authors.initials: V
authors.lastname: Carmon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C408982:CPG-oligonucleotide; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C484963:Tyrobp protein, mouse; D002738:Chloroquine; D020780:Matrix Metalloproteinase 9
keywords: CpG-oligodeoxynucleotide; Toll-like receptor; Triggering receptor expressed on myeloid cells (TREM)-1; macrophage; metalloproteinase (MMP)-9