Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion

Abstract

Clearance of apoptotic cells is the final stage of programmed cell death. Uncleared corpses can become secondarily necrotic, promoting inflammation and autoimmunity. Remarkably, even in tissues with high cellular turnover, apoptotic cells are rarely seen because of efficient clearance mechanisms in healthy individuals. Recently, significant progress has been made in understanding the steps involved in prompt cell clearance in vivo. These include the sensing of corpses via "find me" signals, the recognition of corpses via "eat me" signals and their cognate receptors, the signaling pathways that regulate cytoskeletal rearrangement necessary for engulfment, and the responses of the phagocyte that keep cell clearance events "immunologically silent." This study focuses on our understanding of these steps.

Figure 1.

The steps of efficient apoptotic cell clearance. First, “find me” signals released by apoptotic cells are recognized via their cognate receptors on the surface of phagocytes. This is the sensing stage and stimulates phagocyte migration to the location of apoptotic cells. Second, phagocytes recognize exposed “eat me” signals on the surface of apoptotic cells via their phagocytic receptors, which leads to downstream signaling events culminating in Rac activation. Finally, further signaling events within the phagocyte regulate the digestion and processing of the apoptotic cell meal and the secretion of anti-inflammatory cytokines.

Figure 2.

“Find me” signals and their receptors. Apoptotic cells release “find me” signals including fractalkine, LPC, S1P, and nucleotides. These molecules bind their cognate receptors (CX3CR1, G2A, S1P-R1/5, and P2Y2, respectively) present on the phagocyte surface. “Find me” signal recognition by the phagocyte stimulates migration toward the dying target.

Figure 3.

Apoptotic cell “eat me” signals and phagocytic receptors. As apoptotic cells undergo programmed cell death, they begin to expose “eat me” signals on their surfaces. Phosphatidylserine (PtdSer) is the best studied “eat me” signal; however, several others are also pictured here. “Eat me” signals are recognized by phagocytic engulfment receptors either directly (as with PtdSer receptors including TIM-4, BAI1, and Stabilin-2) or indirectly via bridging molecules or accessory receptors (as with Gas-6/TAM receptors, MFG-E8/α_vβ_3/5, and α_vβ_3/5 in conjunction with CD36 in the recognition of thrombospondin).

Figure 4.

Phagosome maturation: The post-engulfment processing of apoptotic cells. In the first step of phagosome maturation, Dynamin is recruited to the apoptotic cell/phagocyte interface. Dynamin interacts with Vps34, leading to Rab5 recruitment and activation. Activated Rab5 further promotes Vps34 activation, leading to generation of PtdIns(3)P on the phagosome surface (subsequently removed by MTM-1). Mon1a and its binding partner, Ccz1, tie Rab5 activation and Rab7 recruitment to the phagosome. At this stage, the HOPS complex is recruited, leading to Rab7 activation and eventual fusion of the phagosome with the lysosome.