title: Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke.
abstract: OBJECTIVE
  Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive.
  
  
  METHODS
  The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity.
  
  
  RESULTS
  Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic anti-inflammatory signaling in the lung.
  
  
  CONCLUSIONS
  Thus, cholinergic pathways play a pivotal role in the development of pulmonary infections after acute central nervous system injury.
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Odilo
authors.initials: O
authors.lastname: Engel
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Levent
authors.initials: L
authors.lastname: Akyüz
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Andrey C
authors.initials: AC
authors.lastname: da Costa Goncalves
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Winek
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Dames
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Mareike
authors.initials: M
authors.lastname: Thielke
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Chotima
authors.initials: C
authors.lastname: Böttcher
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.).
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.affiliation: From the Department of Experimental Neurology (O.E., K.W., M.T., U.D., A.M.), Department of Neurology (U.D., A.M.), NeuroCure Clinical Research (U.D., A.M.), Institute for Medical Immunology (L.A., C.D., H.D.V., C.M.), BCRT Berlin Brandenburg Centre for Regenerative Medicine (L.A., H.D.V.), Department of Neuropsychiatry and Laboratory of Molecular Psychiatry (C.B., J.P.), and Center for Stroke Research Berlin (O.E., K.W., M.T., U.D., A.M.), Charité University Medicine Berlin, Berlin, Germany; German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (J.P., U.D.); Department of Internal Medicine II, Justus-Liebig-University, Universities Giessen and Marburg Lung Center, Member of the German Center for Lung Research (DZL) (S.H.); and Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.C.d.C.G.). andreas.meisel@charite.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000382:microbiology; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000276:immunology; D010277:Parasympathomimetics / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000276:immunology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction; D020521:Stroke / Q000276:immunology; D014628:Vagotomy
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C402445:Chrna9 protein, mouse; D018722:Nicotinic Agonists; C498513:PNU-282987; D010277:Parasympathomimetics; D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: bone marrow chimeric mice; cholinergic anti-inflammatory pathway; parasympathetic nervous system; pneumonia; stroke-induced immunodepression