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

Grabiec, Aleksander M.; Hussell, Tracy

The logic behind possessing so many receptors that can recognise apoptotic cells is not entirely clear. Some, such as TIM-4, act as tethering receptors without any signalling consequences [41] , similar to CD14 [42] . Different receptors may also act at different stages of efferocytosis [43] or may preferentially clear cells in different locations. For example, TREM2 and TREM2-L form a receptor-ligand pair connecting microglia with apoptotic neurons, directing removal of damaged cells to allow repair [44] . It is also likely that an alternate outcome is required upon efferocytosis that requires linkage to different signalling components [31] . With regard to the TAM receptors, MerTK is ubiquitously expressed on macrophages and even used as a defining marker for them. Airway macrophages, however, unlike most other macrophages, constitutively express Axl, possibly due to the local environment that is rich in granulocyte-macrophage colony-stimulating factor (GM-CSF) [2] . Importantly, receptors that recognise apoptotic cells can also play a dual function: inducing the cytoskeletal rearrangements necessary to ingest the apoptotic cell and also transmitting an instructive signal [45] . It is interesting to note that individual TAM receptor family members use different molecules to bridge them to PtdSer externalised on apoptotic cells: MerTK and Tyro3 are activated by both Gas6 and Protein S, whereas the sole ligand for Axl is Gas6 [46, 47] . In the case of MerTK and Tyro3, it is therefore possible that specific signals triggered by receptor ligation might differ depending on the bridging molecule, though this possibility remains to be verified experimentally. Finally, further selectivity of response is afforded by co-operation of multiple receptors such as Axl and LRP-1 on dendritic cells where Axl tethers the apoptotic cell to dendritic cells, but LRP-1 is required to trigger internalisation [48] .