Cigarette smoke impairs phagocytosis of apoptotic neutrophils by alveolar macrophages via inhibition of the histone deacetylase/Rac/CD9 pathways

Abstract

Efferocytosis, which is the homeostatic phagocytosis of apoptotic cells, prevents the release of toxic intracellular contents and subsequent tissue damage. Impairment of efferocytosis was reported in alveolar macrophages (AMs) of patients with chronic obstructive pulmonary disease (COPD), a common disease caused by smoking. In COPD, histone deacetylase (HDAC) activity is reduced in AMs. We investigated whether the reduction of HDAC activity is associated with the impairment of efferocytosis. Murine AMs were collected by bronchoalveolar lavage and their ability to efferocytose apoptotic human polymorphonuclear leukocytes was assessed. Pre-treatment of AMs with cigarette smoke extract (CSE) or trichostatin A (TSA), an HDAC inhibitor, suppressed efferocytosis and CSE reduced HDAC activity. TSA inhibited the activity of Rac, a key mediator of efferocytosis. These TSA-induced impairments were restored by treatment of AMs with aminophylline, a potent activator of HDAC. To further elucidate the underlying mechanism, we explored a role of CD9 in TSA-induced impairment of efferocytosis. CD9 is a transmembrane protein of the tetraspanin family that facilitates the uptake of several pathogens and other material. TSA profoundly down-regulated the expression of CD9 on AMs. The expression of CD9 was partly down-regulated by the Rac inhibitor. Pretreatment with an anti-CD9 mAb or CD9 small interfering RNA inhibited efferocytosis, which was attributable to the reduced binding of AMs to apoptotic cells. These results suggest that smoking impairs efferocytosis via inhibition of HDAC/Rac/CD9 pathways. Aminophylline/theophylline is effective in restoring the impairment of efferocytosis and might have benefit for the treatment of patients with COPD.

Advanced Role of Neutrophils in Common Respiratory Diseases

“…CD9, a transmembrane protein of the tetraspanin family, facilitates some pathogens and other foreign matters. HDAC and Rac have already been demonstrated that they are required for efferocytosis [100]. Noda et al reported that smoking could impair efferocytosis of neutrophils via inhibition of HDAC/Rac/CD9 pathways (Figure 2, c4).…”

“…Neutrophils contain a great deal of proteases, inflammatory mediators, and oxidants [100]. IL-22/IL-22R signaling pathway plays a pivotal role in antimicrobial defense.…”

“…Noda et al reported that smoking could impair efferocytosis of neutrophils via inhibition of HDAC/Rac/CD9 pathways (Figure 2, c4). The following release of toxic intracellular contents from apoptotic neutrophils could cause tissue damage [100] (Figure 2, d).…”

Recovery from pneumonia requires efferocytosis which is impaired in smokers and those with low body mass index and enhanced by statins

“…7 Statins cause the enzymes Rac and RhoA to sequester derived from the model, as is the BMI-dependent slope of 0.6. From these lines, it can be seen that without statins the differences between smoking status are large, but with statins the differences are smaller.…”

“…7 Statins cause the enzymes Rac and RhoA to sequester Figure 1 Bronchoscopy flow chart. Approximately half of the subjects assessed were deemed ineligible for research bronchoscopy-the majority of those being excluded on safety grounds due to comorbidity.…”