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

Grabiec, Aleksander M.; Hussell, Tracy

Second, many pathogens survive intracellularly, and phagocytosis of infected host cells undergoing apoptosis has diverse consequences for pathogen survival and immune response of the host [119] . One of the main strategies of the immune system to control intracellular infections is through induction of apoptosis of infected cells, which are then engulfed and destroyed together with the pathogen by phagocytes (Fig. 1d) . However, in some cases, efferocytosis of infected cells is used by intracellular pathogens, such as the parasite Leishmania major, to evade the immune response and gain entry into the new cellular host [119] . Among pathogens important in respiratory diseases, the role of efferocytosis has been most thoroughly studied in the context of Mycobacterium tuberculosis infections. M. tuberculosis infects macrophages and induces necrosis of the host cell to avoid clearance by the immune system and disseminate [120] . Interestingly, M. tuberculosis-infected mouse macrophages which die by apoptosis are rapidly efferocytosed by uninfected macrophages, leading to bacterial killing and elimination [121] . This bactericidal effect is dependent on efferocytosis, as the uptake of naked M. tuberculosis does not allow for lysosome recruitment to the bacteriacontaining phagosome, and inhibition of apoptotic cell uptake with a TIM-4-blocking antibody prevents bacterial control in vitro and increases bacterial burden in the lungs in vivo [121] . The observation that bactericidal activity of macrophages infected with Streptococcus pneumoniae is dependent on induction of macrophage apoptosis suggests that a similar mechanism might be involved in controlling infection with this bacterium [122] , though the involvement of efferocytosis in this process has not been formally proven. Engulfment of macrophage-derived apoptotic vesicles also plays a critical, though indirect, role in the adaptive immune response against M. tuberculosis: annexin A1-dependent uptake of apoptotic cells by dendritic cells is required for cross-presentation and generation of M. tuberculosis-specific CD8 T cell response and bacterial clearance from the lung [123] .