Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways

Abstract

Prompt and efficient clearance of apoptotic cells is necessary to prevent secondary necrosis of dying cells and to avoid immune responses to autoantigens. Recent studies have shed light on how apoptotic cells through soluble "find-me" signals advertise their presence to phagocytes at the earliest stages of cell death. Phagocytes sense the find-me signal gradient, and in turn the presence of dying cells, and migrate to their vicinity. The apoptotic cells also expose specific "eat-me" signals on their surface that are recognized by phagocytes through specific engulfment receptors. This review covers the recent progress in the areas of find-me and eat-me signals and how these relate to prompt and immunologically silent clearance of apoptotic cells.

Figure 1. Find-me signals in phagocyte attraction

The known find-me signals released by apoptotic cells are depicted. Of these, the nucleotides and P2Y2, and the CX3CL1 and CX3CR1 modules have been shown to be operational in vivo, but the roles of S1P and LPC remain to be established in an in vivo model. The receptor LPC, although suggested to be G2A, is unclear and remains to be proven.

Figure 2. A balance between find-me signals and keep-out signals

Apoptotic cells release both find-me and keep-out signals that help preferentially recruit monocytes or non-inflammatory cells over neutrophils. Lactoferrin is identified as one of the keep-out signals. It remains to be determined whether lactoferrin may be ‘disabled’ in necrotic cells that promote inflammation.

Figure 3. PANX1 dependent release of nucleotides from apoptotic cells

A specific proteolytic site within the cytoplasmic tail of PANX1 has been identified as a target of executioner caspases 3 and 7 during apoptosis (scissors). This leads to opening of the channel and the release of nucleotides ATP and UTP from the apoptotic cells. Please note that PANX1 is thought to function as a hexamer and that the multi-subunit complex forms a channel through which nucleotides are released across the plasma membrane.

Figure 4. Direct and indirect recognition of phosphatidylserine on apoptotic cells

Two modes of recognition of PtdSer exposed on apoptotic cells involve the direct recognition by phagocytic receptors such as BAI1, TIM-4 and Stabilin 2, and the indirect recognition where bridging molecules such as MFG-E8 and Gas6 bind PtdSer that are in turn recognized by membrane proteins such as MER and α_vβ₃. The two modes of recognition are not mutually exclusive and likely occur simultaneously. Also, for the sake of clarity only the PtdSer recognition is shown here, but there are number of other ligands on apoptotic cells and their cognate receptors on phagocytes have also been identified that may also participate in the specific recognition process.