title: Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules.
abstract: Triggering receptor expressed on myeloid cells-1 (TREM-1) is critical for inflammatory signal amplification. Humans have two forms of TREM-1: a membrane receptor, associated with the adaptor DAP12, and a soluble receptor detected at times of infection. The membrane receptor isoform acts synergistically with the TLR pathway to promote cytokine secretion and neutrophil migration, whereas the soluble receptor functions as a counterregulatory molecule. In multiple models of sepsis, exogenous administration of soluble forms of TREM-1 attenuates inflammation and markedly improves survival. Despite intense interest in soluble TREM-1, both as a clinical predictor of survival and as a therapeutic tool, the origin of native soluble TREM-1 remains controversial. Using human neutrophils, we identified a 15-kDa TREM-1 isoform in primary (azurophilic) and secondary (specific) granules. Mass spectrometric analysis, ELISA, and immunoblot confirm that the 15-kDa protein is a novel splice variant form of TREM-1 (TREM-1sv). Neutrophil stimulation with Pseudomonas aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv. The addition of exogenous TREM-1sv inhibited TREM-1 receptor-mediated proinflammatory cytokine production. Thus, these data reveal that TREM-1 isoforms simultaneously activate and inhibit inflammation via the canonical membrane TREM-1 molecule and this newly discovered granular isoform, TREM-1sv.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Sankar
authors.initials: S
authors.lastname: Baruah
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Kathy
authors.initials: K
authors.lastname: Keck
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Michelle
authors.initials: M
authors.lastname: Vrenios
authors.affiliation: Carver College of Medicine Proteomics Facility, University of Iowa, Iowa City, IA 52242; and.
authors.forename: Marshall R
authors.initials: MR
authors.lastname: Pope
authors.affiliation: Veenstra & Kimm, Inc., Coralville, IA 52241.
authors.forename: Merideth
authors.initials: M
authors.lastname: Pearl
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Kevin
authors.initials: K
authors.lastname: Doerschug
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242; julia-klesney-tait@uiowa.edu.
authors.forename: Julia
authors.identifier: http://orcid.org/0000-0002-0261-8395
authors.initials: J
authors.lastname: Klesney-Tait
mesh_terms: D015550:Cell Degranulation; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology; D008562:Membrane Glycoproteins / Q000302:isolation & purification / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism* / Q000382:microbiology; D020033:Protein Isoforms / Q000302:isolation & purification / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D011971:Receptors, Immunologic / Q000302:isolation & purification / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D051193:Toll-Like Receptors; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C061110:N-palmitoyl-5,6-dipalmitoylcysteinyl-alanyl-glycine