title: Transepithelial migration of neutrophils into the lung requires TREM-1.
abstract: Acute respiratory infections are responsible for more than 4 million deaths each year. Neutrophils play an essential role in the innate immune response to lung infection. These cells have an armamentarium of pattern recognition molecules and antimicrobial agents that identify and eliminate pathogens. In the setting of infection, neutrophil triggering receptor expressed on myeloid cells 1 (TREM-1) amplifies inflammatory signaling. Here we demonstrate for the first time that TREM-1 also plays an important role in transepithelial migration of neutrophils into the airspace. We developed a TREM-1/3-deficient mouse model of pneumonia and found that absence of TREM-1/3 markedly increased mortality following Pseudomonas aeruginosa challenge. Unexpectedly, TREM-1/3 deficiency resulted in increased local and systemic cytokine production. TREM-1/3-deficient neutrophils demonstrated intact bacterial killing, phagocytosis, and chemotaxis; however, histologic examination of TREM-1/3-deficient lungs revealed decreased neutrophil infiltration of the airways. TREM-1/3-deficient neutrophils effectively migrated across primary endothelial cell monolayers but failed to migrate across primary airway epithelia grown at the air-liquid interface. These data define a new function for TREM-1 in neutrophil migration across airway epithelial cells and suggest that it amplifies inflammation through targeted neutrophil migration into the lung.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 200 Hawkins Dr., Iowa City, Iowa 52242, USA. juliaklesney-tait@uiowa.edu
authors.forename: Julia
authors.initials: J
authors.lastname: Klesney-Tait
authors.forename: Kathy
authors.initials: K
authors.lastname: Keck
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Li
authors.forename: Susan
authors.initials: S
authors.lastname: Gilfillan
authors.forename: Karel
authors.initials: K
authors.lastname: Otero
authors.forename: Sankar
authors.initials: S
authors.lastname: Baruah
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Steven M
authors.initials: SM
authors.lastname: Varga
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Knudson
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Moninger
authors.forename: Jessica
authors.initials: J
authors.lastname: Moreland
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
mesh_terms: D000818:Animals; D008168:Lung / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011550:Pseudomonas aeruginosa; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; C447602:Trem3 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1