title: Reversal of TREM-1 ectodomain shedding and improved bacterial clearance by intranasal metalloproteinase inhibitors.
abstract: Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on neutrophils and monocyte/macrophages and amplifies Toll-like receptor-mediated inflammation during infection. TREM-1 also exists in an antagonistic soluble form (sTREM-1) that has been used as a peripheral biomarker in sepsis, though the mechanisms of its release are not entirely clear. The requirement of TREM-1 in single microbial infections is controversial, with some studies showing a protective role and others a contribution to immunopathology. Furthermore, the role of membrane-bound and sTREM-1 in polygenic infections is currently unknown. In a mouse co-infection model where preceding viral infection greatly enhances bacteria co-infection, we now determine a mechanisms for the striking increase in sTREM-1 and the loss of TREM-1 on surface of neutrophils. We identified a matrix metalloproteinase (MMP)-9 cleavage site in TREM-1 and that the increase of MMP-9 in bronchoalveolar lavage fluid mirrors sTREM-1 release. In vitro studies with neutrophils and MMP-9 and the reduction of sTREM-1 in vivo after MMP-9 inhibition verifies that this enzyme cleaves TREM-1. Intriguingly, MMP-9 inhibition significantly reduces bacterial load and ensuing immunopathology in a co-infection model. This highlights MMP-9 inhibition as a potential therapeutic via blocking cleavage of TREM-1.
authors.affiliation: National Heart and Lung Institute, Department of Inflammation, Development &Repair, Imperial College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Weiss
authors.affiliation: National Heart and Lung Institute, Department of Inflammation, Development &Repair, Imperial College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Lai
authors.affiliation: Manchester Collaborative Centre for Inflammation Research (MCCIR), Manchester, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Fife
authors.affiliation: Manchester Collaborative Centre for Inflammation Research (MCCIR), Manchester, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Grabiec
authors.affiliation: National Heart and Lung Institute, Department of Inflammation, Development &Repair, Imperial College London, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Tildy
authors.affiliation: National Heart and Lung Institute, Department of Inflammation, Development &Repair, Imperial College London, London, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Snelgrove
authors.affiliation: National Heart and Lung Institute, Department of Inflammation, Development &Repair, Imperial College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Xin
authors.affiliation: National Heart and Lung Institute, Department of Inflammation, Development &Repair, Imperial College London, London, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Lloyd
authors.affiliation: National Heart and Lung Institute, Department of Inflammation, Development &Repair, Imperial College London, London, UK.|Manchester Collaborative Centre for Inflammation Research (MCCIR), Manchester, UK.
authors.forename: T
authors.initials: T
authors.lastname: Hussell
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D058491:Bacterial Load / Q000187:drug effects; D002478:Cells, Cultured; D060085:Coinfection; D004195:Disease Models, Animal; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000378:metabolism*; D010666:Phenylpropionates / Q000627:therapeutic use*; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000378:metabolism*; D000072417:Protein Domains; D059748:Proteolysis / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000502:physiology*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1 / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D008565:Membrane Proteins; D010666:Phenylpropionates; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D020780:Matrix Metalloproteinase 9