title: Impairment of Immunoproteasome Function by Cigarette Smoke and in Chronic Obstructive Pulmonary Disease.
abstract: Patients with chronic obstructive pulmonary disease (COPD) and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I-mediated antigen presentation for the resolution of intracellular infections.
  
  
  
  To characterize immunoproteasome function in COPD and its regulation by cigarette smoke.
  
  
  
  Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors and patients with COPD or idiopathic pulmonary fibrosis (IPF), as well as in cigarette smoke-exposed mice. Smoke-mediated alterations of immunoproteasome activity and MHC I surface expression were analyzed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo.
  
  
  
  Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of patients with COPD and in isolated alveolar macrophages of patients with COPD or IPF. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End-stage COPD lungs showed markedly impaired immunoproteasome activities.
  
  
  
  We here show that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF.
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Ilona E
authors.initials: IE
authors.lastname: Kammerl
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Dann
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mossina
authors.affiliation: 2 Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Brech
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lukas
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Vosyka
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Nathan
authors.affiliation: 3 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the DZL, Neuherberg, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Conlon
authors.affiliation: 2 Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Darcy E
authors.initials: DE
authors.lastname: Wagner
authors.affiliation: 4 Department of Bio-organic Synthesis, Leiden University, Leiden, the Netherlands.
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: 5 Department of Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Prasse
authors.affiliation: 6 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: 7 Biomedical Center, Bioinformatics Unit, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Straub
authors.affiliation: 8 Division of Experimental Asthma Research, Research Center Borstel, Airway Research Center North, Member of the DZL, Borstel, Germany.|9 Institute of Experimental Medicine, Christian-Albrechts-Universität zu Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Krauss-Etschmann
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: 10 Thoraxchirurgisches Zentrum, Klinik für Allgemeine-, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Member of the DZL, Munich, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Preissler
authors.affiliation: 10 Thoraxchirurgisches Zentrum, Klinik für Allgemeine-, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Member of the DZL, Munich, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Winter
authors.affiliation: 11 Asklepios Fachkliniken München-Gauting, Gauting, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Lindner
authors.affiliation: 10 Thoraxchirurgisches Zentrum, Klinik für Allgemeine-, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Member of the DZL, Munich, Germany.|11 Asklepios Fachkliniken München-Gauting, Gauting, Germany; and.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Hatz
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.|11 Asklepios Fachkliniken München-Gauting, Gauting, Germany; and.|12 Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-Maximilians-Universität, Member of the DZL, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Behr
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Heinzelmann
authors.affiliation: 3 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the DZL, Neuherberg, Germany.
authors.forename: Ali Ö
authors.initials: AÖ
authors.lastname: Yildirim
authors.affiliation: 2 Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: 1 Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007162:Immunoproteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000503:physiopathology*; D014026:Nicotiana
chemical_list: D007162:Immunoproteins; D012906:Smoke
keywords: MHC class I antigen presentation; alveolar macrophages; cigarette smoke; immunoproteasome