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-?, 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.

SUBMITTER: Stolberg VR 

PROVIDER: S-EPMC4475455 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature