Phosphatidylethanolamine is a phagocytic ligand implicated in the binding and removal of apoptotic and bacterial extracellular vesicles.

The efficient recognition and removal of apoptotic cells and extracellular vesicles (EVs) by phagocytes is critical to prevent secondary necrosis and maintain tissue homeostasis. Such detection involves receptors and bridging molecules that recognize aminophospholipids-normally restricted to the inner leaflet of healthy cells-which become exposed on the surface of dead cells and the vesicles they produce.1,2,3,4,5 A majority of studies focus on phosphatidylserine (PS), for which there are well-established receptors that either bind to the lipid directly or indirectly via intermediary proteins.6,7,8 Phosphatidylethanolamine (PE) is even more prevalent than PS in the inner leaflet of mammalian cells9 and also becomes exposed by the action of scramblases during cell death,10,11 though little is known about the effects of PE once scrambled. Here, we report that PE can itself serve as a phagocytic ligand for macrophages by engaging CD300 family receptors. CD300a and CD300b specifically modulated the binding and uptake of PE particles, and this process involved immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors and spleen tyrosine kinase (Syk). For bacteria, which contain PE but largely lack PS in their membranes, we report that PE engagement enabled the binding and uptake of spheroplasts and bacterial extracellular vesicles (BEVs) that were unsheathed by the cell wall. The inflammatory responses of macrophages to PE particles containing lipopolysaccharide (LPS) were also curtailed by CD300a expression. Based on these observations, we posit that the direct recognition of PE facilitates mechanisms of clearance that stand to have a broad impact on the immune response.