Putting the brakes on phagocytosis: “don't‐eat‐me” signaling in physiology and disease

Abstract

Timely removal of dying or pathogenic cells by phagocytes is essential to maintaining host homeostasis. Phagocytes execute the clearance process with high fidelity while sparing healthy neighboring cells, and this process is at least partially regulated by the balance of "eat-me" and "don't-eat-me" signals expressed on the surface of host cells. Upon contact, eat-me signals activate "prophagocytic" receptors expressed on the phagocyte membrane and signal to promote phagocytosis. Conversely, don't-eat-me signals engage "anti-phagocytic" receptors to suppress phagocytosis. We review the current knowledge of don't-eat-me signaling in normal physiology and disease contexts where aberrant don't-eat-me signaling contributes to pathology.

The phagocytic cyst cells in Drosophila testis eliminate germ cell progenitors via phagoptosis

“…Activation of neutrophils by pathogens is accompanied by PS exposure on the surface of the activated but viable cells, leading to their phagoptosis. Moreover, old erythrocytes down-regulate CD47, which is expressed on the surface of young cells and acts as a “don’t-eat-me” signal to block phagoptosis ( 8 ). Hence, it was suggested that phagoptosis is induced by the reversible exposure of PS or other eat-me signals, or by the loss of don’t-eat-me protection signals, on the outer leaflet of an otherwise viable cell.…”

Drugging the efferocytosis process: concepts and opportunities

“…The ability of phagocytes to specifically recognize apoptotic cells is based on the exposure of ‘eat-me’ signals on the surface of apoptotic cells, in contrast to ‘do not eat-me’ signals that are exposed on the surface of live cells 27 . The ‘eat-me’ signals are recognized by a cohort of phagocytic receptors as detailed below.…”

“…CD31, expressed on viable cells, via homotypic interactions, is thought to mediate the detachment of live cells from the surface of phagocytes 56 . Although targeting anti-phagocytic receptors to promote efferocytosis of apoptotic cells is less studied, this could also be a powerful approach in the context of ongoing inflammation 27 .…”

Rubicon-deficiency sensitizes mice to mixed lineage kinase domain-like (MLKL)-mediated kidney ischemia-reperfusion injury

“…Phagocytosis of dead or dying cells was studied in detail over the last decade [ 1 , 2 ]. The protein rubicon (RUBCN) was initially demonstrated as an autophagy regulator associated with the protein Beclin-1 [ 3 , 4 ], and later demonstrated to be involved in endosomal maturation [ 5 , 6 ].…”