title: Glucocorticoid-Augmented Efferocytosis Inhibits Pulmonary Pneumococcal Clearance in Mice by Reducing Alveolar Macrophage Bactericidal Function.
abstract: Inhaled corticosteroids (ICS) increase community-acquired pneumonia (CAP) incidence in patients with chronic obstructive pulmonary disease (COPD) by unknown mechanisms. Apoptosis is increased in the lungs of COPD patients. Uptake of apoptotic cells (ACs) ("efferocytosis") by alveolar macrophages (AMøs) reduces their ability to combat microbes, including Streptococcus pneumoniae, the most common cause of CAP in COPD patients. Having shown that ICS significantly increase AMø efferocytosis, we hypothesized that this process, termed glucocorticoid-augmented efferocytosis, might explain the association of CAP with ICS therapy in COPD. To test this hypothesis, we studied the effects of fluticasone, AC, or both on AMøs of C57BL/6 mice in vitro and in an established model of pneumococcal pneumonia. Fluticasone plus AC significantly reduced TLR4-stimulated AMø IL-12 production, relative to either treatment alone, and decreased TNF-α, CCL3, CCL5, and keratinocyte-derived chemoattractant/CXCL1, relative to AC. Mice treated with fluticasone plus AC before infection with viable pneumococci developed significantly more lung CFUs at 48 h. However, none of the pretreatments altered inflammatory cell recruitment to the lungs at 48 h postinfection, and fluticasone plus AC less markedly reduced in vitro mediator production to heat-killed pneumococci. Fluticasone plus AC significantly reduced in vitro AMø killing of pneumococci, relative to other conditions, in part by delaying phagolysosome acidification without affecting production of reactive oxygen or nitrogen species. These results support glucocorticoid-augmented efferocytosis as a potential explanation for the epidemiological association of ICS therapy of COPD patients with increased risk for CAP, and establish murine experimental models to dissect underlying molecular mechanisms.
authors.affiliation: Research Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105;
authors.forename: Valerie R
authors.initials: VR
authors.lastname: Stolberg
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: McCubbrey
authors.affiliation: Research Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Jeanette P
authors.initials: JP
authors.lastname: Brown
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Sean W
authors.initials: SW
authors.lastname: Crudgington
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Sophina H
authors.initials: SH
authors.lastname: Taitano
authors.affiliation: Kalamazoo College, Kalamazoo, MI 49006;
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Saxton
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Mancuso
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Medical Service, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105 jlcurtis@umich.edu.
authors.forename: Jeffrey L
authors.identifier: http://orcid.org/0000-0001-5191-4847
authors.initials: JL
authors.lastname: Curtis
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects*; D000730:Androstadienes / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D000068298:Fluticasone; D005786:Gene Expression Regulation; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D011018:Pneumonia, Pneumococcal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D026361:Reactive Nitrogen Species / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000305:Adrenal Cortex Hormones; D000730:Androstadienes; C496534:Ccl3 protein, mouse; C503460:Ccl5 protein, mouse; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000068298:Fluticasone