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

Grabiec, Aleksander M.; Hussell, Tracy

Activation of TAM receptors by apoptotic cells inhibits production of proinflammatory cytokines, such as TNFα and IL-6, while promoting expression of factors that suppress inflammation and promote tissue repair, including IL-10 and TGF-β. c Some enveloped viruses express PtdSer on their envelopes and use PtdSer recognition receptors, such as TAM and TIM receptor families, to promote infection of the host cells and evade the immune response. d During microbial infections with intracellular pathogens, induction of apoptosis of infected cells is one of the strategies of the host immune system to facilitate pathogen clearance. For example, in case of Mycobacterium tuberculosis (Mtb) infections, necrosis of infected cells leads to dissemination of bacteria, whereas engulfment of infected cells undergoing apoptosis allows for pathogen destruction airways from the periphery during influenza infection contract by Fas-dependent apoptosis, while the number of resident airway macrophages remains unchanged [64] , whereas another implies significant ablation of resident airway macrophages followed by replenishment from the interstitial pool [65] . Discrepancy might arise from the use of intranasal dye (that becomes diluted on cell division) or the depletion by irradiation with the lung protected by lead. In order to track definitively the fate of airway macrophages following influenza infection, the Flt3-Cre × Rosa26-LSL-YFP reporter mice would be useful as all bone marrow emigrants become YFP expressing and so mice do not require prior manipulation to distinguish resident versus recruited airway cells [66] . Like airway macrophages, epithelial cells similarly have a long half-life in health. Using reporter mice where ciliated cells and their progeny can be tracked across their lifetime, a half-life of 6 months in the trachea and 17 months in the bronchioles and terminal bronchioles has been estimated [67] . Taken together, these observations indicate that in homeostasis relatively small quantities of apoptotic cells appear in the airways due to slow turnover of the main cell populations residing in the healthy lung. It is therefore not surprising that lung phagocytes efficiently clear these scarce apoptotic cells even when their efferocytic function is partly disrupted. For example, deletion of Axl, which is highly expressed on murine airway macrophages, does not cause accumulation of necrotic cell debris and lung inflammation in the absence of accompanying infection despite significant impairment of the efferocytic function of airway macrophages [2] . Similarly, blockade of apoptotic cell uptake by airway epithelial cells through cell type-specific deletion of the small GTPase Rac1, which is required for efferocytosis mediated by several classes of engulfment receptors, does not affect the integrity and responses of the epithelial barrier without administration of exogenous apoptotic cells or induction of allergic airway inflammation [68] .