title: Distinct cellular sources of hepoxilin A3 and leukotriene B4 are used to coordinate bacterial-induced neutrophil transepithelial migration.
abstract: Neutrophilic infiltration is a leading contributor to pathology in a number of pulmonary disease states, including cystic fibrosis. Hepoxilin A3 (HXA3) is a chemotactic eicosanoid shown to mediate the transepithelial passage of neutrophils in response to infection in several model systems and at multiple mucosal surfaces. Another well-known eicosanoid mediating general neutrophil chemotaxis is leukotriene B4 (LTB4). We sought to distinguish the roles of each eicosanoid in the context of infection of lung epithelial monolayers by Pseudomonas aeruginosa. Using human and mouse in vitro transwell model systems, we used a combination of biosynthetic inhibitors, receptor antagonists, as well as mutant sources of neutrophils to assess the contribution of each chemoattractant in driving neutrophil transepithelial migration. We found that following chemotaxis to epithelial-derived HXA3 signals, neutrophil-derived LTB4 is required to amplify the magnitude of neutrophil migration. LTB4 signaling is not required for migration to HXA3 signals, but LTB4 generation by migrated neutrophils plays a significant role in augmenting the initial HXA3-mediated migration. We conclude that HXA3 and LTB4 serve independent roles to collectively coordinate an effective neutrophilic transepithelial migratory response.
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA 02129; Department of Pediatrics, Harvard Medical School, Boston, MA 02115;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pazos
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA 02129; Department of Pediatrics, Harvard Medical School, Boston, MA 02115;
authors.forename: Waheed
authors.initials: W
authors.lastname: Pirzai
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA 02129; Department of Pediatrics, Harvard Medical School, Boston, MA 02115;
authors.forename: Lael M
authors.initials: LM
authors.lastname: Yonker
authors.affiliation: Department of Entomology and University of California Davis Comprehensive Cancer Center, University of California, Davis, CA 95616; and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Vision Science Program, School of Optometry, University of California at Berkeley, Berkeley, CA 94720.
authors.forename: Karsten
authors.initials: K
authors.lastname: Gronert
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA 02129; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; bphurley@partners.org.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Hurley
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001419:Bacteria / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology; D020013:Calcium Signaling; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism*; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000276:immunology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics / Q000276:immunology*
chemical_list: C513240:LTB4R protein, human; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D015126:8,11,14-Eicosatrienoic Acid