The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation

Grabiec, Aleksander M.; Hussell, Tracy

In a series of elegant studies, Hodge and co-workers demonstrate that increases in the numbers of apoptotic cells detected in the lungs of patients with COPD can be attributed to significantly impaired efferocytic function of airway macrophages. Uptake of apoptotic bronchial epithelial cells and neutrophils is significantly reduced in bronchoalveolar lavage macrophages from patients with COPD compared to healthy controls [21, 22, 79] , and this defect is more pronounced in COPD patients who currently smoke [22] . The observed reductions in efferocytic potential of airway macrophages in vitro correlate with the frequency of apoptotic bronchial epithelial cells isolated from bronchial brushings and are associated with altered expression of several proteins involved in apoptotic cell recognition and binding, including CD31, CD44 and LRP-1/CD91 [22] . Intriguingly, restoration of COPD airway macrophage efferocytic function by the macrolide antibiotic azithromycin does not correlate with changes in expression of these molecules [21] . Instead, it depends on PtdSer binding by airway macrophages [21] , suggesting that deregulation of PtdSer-recognising receptors or bridging molecules might be responsible for defective apoptotic cell removal in COPD. Neither TAM nor TIM families of PtdSer recognition receptors have been studied in COPD so far but, surprisingly, increased expression of MerTK is observed on airway macrophages from cigarette smokers [18] , which are also characterised by impaired apoptotic cell uptake compared to cells from healthy nonsmokers [18, 22] . This observation indicates that upregulation of MerTK is not sufficient to restore the efforocytic function of airway macrophages to normal levels and other PtdSer receptors, such as Axl, which is highly expressed on mouse airway macrophages [2] , might play a more prominent role.