Redistribution of the glycocalyx exposes phagocytic determinants on apoptotic cells

Phagocytes remove dead and dying cells by engaging “eat-me” ligands such as phosphatidylserine (PtdSer) on the surface of apoptotic targets. However, PtdSer is obscured by the bulky exofacial glycocalyx, which also exposes ligands that activate “don’t-eat-me” receptors such as Siglecs. Clearly, unshielding the juxtamembrane “eat-me” ligands is required for the successful engulfment of apoptotic cells, but the mechanisms underlying this process have not been described. Using human and murine cells, we find that apoptosis-induced retraction and weakening of the cytoskeleton that anchors transmembrane proteins cause an inhomogeneous redistribution of the glycocalyx: actin-depleted blebs emerge, lacking the glycocalyx, while the rest of the apoptotic cell body retains sufficient actin to tether the glycocalyx in place. Thus, apoptotic blebs can be engaged by phagocytes and are targeted for engulfment. Therefore, in cells with an elaborate glycocalyx, such as mucinous cancer cells, this “don’t-come-close-to-me” barrier must be removed to enable clearance by phagocytosis. [Display omitted] •The glycocalyx can shield “eat-me” ligands exposed on the surface of apoptotic cells•The glycocalyx is segregated away from apoptotic blebs to prime efferocytosis•Reorganization of the cytoskeleton causes the redistribution of the glycocalyx Le et al. report that during apoptosis, the plasmalemma-associated cytoskeleton redistributes and weakens, leading to the formation of blebs denuded of the glycocalyx. Displacement of the bulky glycocalyx, which can obstruct the access of phagocytes, enables the engulfment of apoptotic cells, including those with a rich glycocalyx, such as mucinous tumors.