Glucocorticoid-Augmented Efferocytosis Inhibits Pulmonary Pneumococcal Clearance in Mice by Reducing Alveolar Macrophage Bactericidal Function

Abstract

Inhaled corticosteroid(s) (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 (AC) (“efferocytosis”) by alveolar macrophages (AMø) 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 (GCAE), 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 AMø 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 KC, relative to AC. Mice treated with fluticasone plus AC before infection with viable pneumococci developed significantly more lung CFU at 48 h. However, none of the pretreatments altered inflammatory cell recruitment to the lungs at 48 h post-infection, 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 GCAE as a potential explanation for the epidemiological association of ICS therapy of COPD patients with increased risk of CAP, and establish murine experimental models to dissect underlying molecular mechanisms.

Pulmonary macrophages: key players in the innate defence of the airways

“…Furthermore, removal of dead/dying cells by AMs results in subsequent impaired phagocytosis and bacterial killing and impaired clearance of S. pneumoniae. 24 Moreover, it has been shown that administration of glucocorticoids during active murine pneumonia infection further hinders the ability of AMs to kill bacteria via inhibition of cytokine production 25. This highlights the complexity of glucocorticoid treatment in patients with chronic lung disease and a role for AMs in susceptibility to secondary infection and exacerbation.…”

Purified Streptococcus pneumoniae Endopeptidase O (PepO) Enhances Particle Uptake by Macrophages in a Toll-Like Receptor 2- and miR-155-Dependent Manner

“…Decreased macrophage trafficking in infants results in delayed clearance of pneumococcal colonization (9). Reducing the bactericidal function of alveolar macrophages with glucocorticoid leads to inhibition of pulmonary pneumococcal clearance in mice (10), while promoting CCL2-mediated macrophage recruitment with macrolides accelerates clearance of nasopharyngeal pneumococcal colonization in mice (11). Although the significance of macrophages in clearance of pneumococci has been well established, the related molecular mechanisms remain poorly understood.…”

AMPKα1 is essential for Glucocorticoid Receptor triggered anti-inflammatory macrophage activation

“…GC/GR signaling enhances the efferocytic properties of macrophages (Giles et al, 2001;Heasman et al, 2003;Stolberg et al, 2015), for instance, by increasing the expression of Mertk or Anxa1 as a core aspect of their anti-inflammatory effects (Koenen et al, 2018;Yona and Gordon, 2007;Zizzo et al, 2012). Efferocytosis is associated with macrophage polarization state since it induces the acquisition of an anti-inflammatory/resolving phenotype (Fadok et al, 1998;Han et al, 2016;Huynh et al, 2002;Zhang et al, 2019a), thus provides a bridge in macrophage function across sterile and LPS induced inflammation.…”