title: DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation.
abstract: Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell membrane-associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia/reperfusion injury (IRI), we took advantage of a clinically relevant mouse model of transplant-mediated lung IRI. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient, deficiency in DAP12 protected against pulmonary IRI. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking.
authors.affiliation: Department of Surgery, Washington University, St. Louis, MO 63110;
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Spahn
authors.affiliation: Department of Surgery, Washington University, St. Louis, MO 63110;
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Surgery, Washington University, St. Louis, MO 63110;
authors.forename: Alejandro C
authors.initials: AC
authors.lastname: Bribriesco
authors.affiliation: Department of Surgery, Washington University, St. Louis, MO 63110;
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510;
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63110; and.
authors.forename: Aida
authors.initials: A
authors.lastname: Ibricevic
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63110; and.
authors.forename: Jie-Hong
authors.initials: JH
authors.lastname: Pan
authors.affiliation: Department of Pathology & Immunology, Washington University, St. Louis, MO 63110.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Zinselmeyer
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63110; and.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510;
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldstein
authors.affiliation: Department of Surgery, Washington University, St. Louis, MO 63110;
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Krupnick
authors.affiliation: Department of Surgery, Washington University, St. Louis, MO 63110; Department of Pathology & Immunology, Washington University, St. Louis, MO 63110.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63110; and.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Miller
authors.affiliation: Department of Surgery, Washington University, St. Louis, MO 63110; Department of Pathology & Immunology, Washington University, St. Louis, MO 63110 kreiseld@wudosis.wustl.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D054426:Chemokine CXCL2 / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000473:pathology; D016040:Lung Transplantation; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D055031:Primary Graft Dysfunction / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C484963:Tyrobp protein, mouse