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

Grabiec, Aleksander M.; Hussell, Tracy

Apoptotic cells expose a variety of molecules on their cell surface that can be recognised by receptors on phagocytic cells. The precise composition of such 'eat-me' signals likely depends on whether apoptosis is occurring under homeostatic conditions or during inflammation and is tissue-and cell type-specific [1, 8] . One of the best studied 'eat-me' signals is phosphatidylserine (PtdSer) that in living cells is localised to the inner leaflet of the plasma membrane and is externalised upon induction of apoptosis [9] . Overexpression of PtdSer enhances apoptotic cell engulfment, whereas PtdSer blockade suppresses this process, leading to autoimmunity [10, 11] . Irreversible externalisation occurs when caspases inactivate flippase (ATP11C) that in healthy cells continually flips PtdSer in the plasma membrane [12] . At the same time, caspase-dependent activation of scramblases (such as Xkr8), which non-specifically and bi-directionally scramble phospholipids in the plasma membrane, is also required for PtdSer exposure on apoptotic cells [13] . PtdSer is transiently exposed on the surface of living cells that resist efferocytosis, suggesting that this signal alone may not be enough, or that prolonged interaction of PtdSer receptors on phagocytes is required [14] . Oxidised low-density lipoprotein, calreticulin, annexin A1, ICAM3, C1q and thrombospondin-1 (TSP1) are also implicated in efferocytosis [1] . Furthermore, healthy cells prevent engulfment by expressing CD47 and CD31 [15, 16] or by ligating CD300a that impedes macrophage function [17] . A balance of efferocytosis-inducing and inhibitory signals may therefore determine apoptotic cell clearance.