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

Grabiec, Aleksander M.; Hussell, Tracy

Apart from potential alterations in PtdSer receptor expression and function, which require more detailed studies, several other mechanisms might be involved in efferocytosis defects observed in COPD. Significant impairment of apoptotic cell uptake by airway macrophages from smokers indicates an important role of oxidative stress caused by cigarette smoke components in this process [18, 22] . In mice, cigarette smoke exposure, which is sufficient to induce emphysema [80] , significantly suppresses efferocytosis by airway macrophages in vivo and in vitro, and this effect is reversible by treatment with antioxidants or overexpression of extracellular superoxide dismutase [81, 82] . Macrophage phagocytosis of apoptotic cells is also inhibited by the alarmin high mobility group protein-1 (HMGB1) [83, 84] , and elevated levels of HMGB1 both in the airways and peripheral blood of patients with COPD have recently been reported, negatively correlating with patient lung function [20, 85] . Since necrotic cells are the main source of extracellular HMGB1, a positive feedback loop might exist in COPD where apoptotic cells undergo secondary necrosis and release HMGB1, which further impairs the efferocytic function of airway macrophages. This in turn would lead to accumulation of greater amounts of necrotic debris and perpetuation of chronic inflammation. Finally, engulfment of apoptotic cells by macrophages is also regulated by the members of the collectin family of C-type lectins. The levels of mannose-binding lectin (MBL), which promotes apoptotic cell uptake in vitro [86] , are reduced in the airways of patients with COPD and correlate with impaired macrophage efferocytosis [87, 88] . Surfactant protein A (SP-A) and SP-D, on the other hand, play a more complex role in apoptotic cell recognition in the lung. While homeostatic interaction of SP-A or SP-D with signal inhibitory regulatory protein-α (SIRPα) expressed on airway macrophages suppresses efferocytosis [89] , opsonisation of apoptotic cells by SP-A or SP-D and interaction of this complex with LRP-1/CD91 enhances apoptotic cell uptake [29, 90] . The latter seems to play a more prominent role during chronic lung inflammation as SP-D levels are significantly reduced in patients with COPD [28, 91] , potentially contributing to efferocytosis defects. Alternatively, downregulation of SP-D might represent a physiological response of the lung aimed at overcoming SIRPα-dependent suppression of macrophage efferocytic function in the presence of large amounts of dead cells, which fail to efficiently remove apoptotic cells from the COPD airways due to other phagocytosis defects.