title: Restoring cigarette smoke-induced impairment of efferocytosis in alveolar macrophages.
abstract: Cigarette smoke has been associated with susceptibility to different pulmonary and airway diseases. Impaired alveolar macrophages (AMs) that are major phagocytes in the lung have been associated with patients with airway diseases and active smokers. In the current report, we show that exposure to second-hand cigarette smoke (SHS) significantly reduced efferocytosis in vivo. More importantly, delivery of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) to the alveolar space restored and refurbished the efferocytosis capability of AMs. Exposure to SHS significantly reduced expression of CD16/32 on AMs, and treatment with GM-CSF not only restored but also significantly increased the expression of CD16/32 on AMs. GM-CSF treatment increased uptake and digestion/removal of apoptotic cells by AMs. The latter was attributed to increased expression of Rab5 and Rab7. Increased efferocytosis of AMs was also tested in a disease condition. AMs from GM-CSF-treated, influenza-infected, SHS-exposed mice showed significantly better efferocytosis activity, and mice had significantly less morbidity compared with phosphate-buffered saline-treated group. GM-CSF-treated mice had increased amphiregulin levels in the lungs, which in addition to efferocytosis of AMs may have attributed to their protection against influenza. These results will have great implications for developing therapeutic approaches by harnessing mucosal innate immunity to treat lung and airway diseases and protect against pneumonia.
authors.affiliation: Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: R
authors.initials: R
authors.lastname: Subramaniam
authors.affiliation: Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: S
authors.initials: S
authors.lastname: Keshava
authors.affiliation: Biomedical research, The University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: P
authors.initials: P
authors.lastname: Neuenschwander
authors.affiliation: Center for Pulmonary and Infectious Diseases Control (CPIDC), The University of Texas Health Science Center at Tyler, Tyler, Texas, USA.
authors.forename: H
authors.initials: H
authors.lastname: Shams
mesh_terms: D066258:Amphiregulin / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D010587:Phagocytosis; D012907:Smoking / Q000009:adverse effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D066258:Amphiregulin; D014028:Tobacco Smoke Pollution; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins