Table 1.
Molecular machinery of apoptotic cell recognition
| SIGNAL | RELEASE/EXPOSURE MECHANISM | RECOGNITION MECHANISM | DETAILS/COMMENTS | REFERENCE |
|---|---|---|---|---|
| ‘Find-me’ | ||||
| Nucleotides | PANX1 | P2Y2 | Release of ATP/UTP from apoptotic cells promotes monocyte and macrophage migration in vitro and in vivo. Other P2Y family members may also facilitate detection of nucleotides by phagocytes. | 15,16 |
| LPC | ? | G2A | Caspase 3-mediated activation of iPLA2 is also necessary to generate LPC during apoptosis. LPC augments monocyte migration in vitro. | 18 |
| SIP | ? | ? | Purified SIP enhances monocyte and macrophage migration in vitro. | 19 |
| ICAM-3 | Microparticles | ? | ICAM-3 localizes to apoptotic blebs and microparticles during apoptosis. ICAM-3 may also facilitate tethering of apoptotic B cells to macrophages. | 21,184 |
| CX3CL1 | Microparticles | CX3CR1 | CX3CL1/CX3CR1 participates in the recruitment of macrophages to lymphoid follicles undergoing germinal center reactions. | 22 |
| EMAP II | ? | ? | Generation and release of mature EMAP II occurs during apoptosis. The ability of apoptotic cell-derived EMAP II to promote phagocyte migration has not been examined directly. | 185 |
| Annexin A1 | Membrane lysis | ? | Release and proteolytic processing of annexin A1 by ADAM10 during secondary necrosis promotes migration of monocytes. Annexin A1 may also participate in the engulfment step of apoptotic cell clearance. | 186,187 |
| ‘Keep-out’ | ||||
| Lactoferrin | ? | ? | Release from apoptotic cells to inhibit neutrophil migration. | 23 |
| ‘Eat-me’ | ||||
| PtdSer | Phospholipid scramblase/amino-phospholipid translocase? | BAI1 | BAI1 functions upstream of the ELMO1-Dock180-Rac module to mediate apoptotic cell recognition and engulfment. BAI1 interacts with PtdSer though its thrombospondin type 1 repeats. | 30 |
| TIM1/3/4 | Metal-ion-dependent ligand binding site located in the IgV domain of TIM-4 mediates PtdSer binding. TIM-3 may also play an important role in regulating cross-presentation of apoptotic cell-associated antigens by CD8+DCs. | 33–35 | ||
| Stabilin-2 | Stabilin-2 functions upstream of GULP and thymosin β4 to aid apoptotic cell clearance. Stabilin-2 binds PtdSer via its epidermal growth factor-like domain repeats. | 31,32,36,37 | ||
| MFG-E8 – αVβ3 | MFG-E8 is secreted by ‘activated’ macrophage and immature DCs to promote apoptotic cell engulfment. MFG-E8 interacts with PtdSer and αVβ3 via its factor-VIII-homologous domains and RGD motif, respectively. | 40 | ||
| Protein S/Gas6 – Tryo-3/Axl/Mer | Protein S and Gas6 interact with PtdSer and TAM receptors via their Gla domains and sex hormone binding globulin domains, respectively. Usage of different TAM receptors is dependent on phagocyte and organ type. | 39,41,188,189 | ||
| RAGE | RAGE is thought to function upstream of Rac1 to aid apoptotic cell recognition and uptake by alveolar macrophages. | 190 | ||
| CRT | Exocytic? | CD91 | Conditions that can induce both apoptosis and ER stress can facilitate pre-apoptotic exposure of CRT. | 42,44,191 |
| ‘Don’t eat-me’ | ||||
| CD31 | N/A | CD31 | Homophilic interaction of CD31 on leukocytes and macrophages promotes cell detachment. How signalling-disabled CD31 are generated on apoptotic leukocytes is unknown. | 192 |
| CD47 | N/A | SIRP α | Besides functioning as a ‘don’t eat-me signal’, evidence also suggest that CD47 on apoptotic lymphocytes could aid apoptotic cell binding to macrophages. | 42,193 |