Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Jan 1;5(1):a008748.
doi: 10.1101/cshperspect.a008748.

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

Affiliations
Review

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

Amelia Hochreiter-Hufford et al. Cold Spring Harb Perspect Biol. .

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.

PubMed Disclaimer

Figures

Figure 1.
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.
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.
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/αvβ3/5, and αvβ3/5 in conjunction with CD36 in the recognition of thrombospondin).
Figure 4.
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.

Similar articles

Cited by

References

    1. Aderem A, Underhill DM 1999. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17: 593–623 - PubMed
    1. Akakura S, Singh S, Spataro M, Akakura R, Kim JI, Albert ML, Birge RB 2004. The opsonin MFG-E8 is a ligand for the αvβ5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells. Exp Cell Res 292: 403–416 - PubMed
    1. Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N 1998. Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188: 1359–1368 - PMC - PubMed
    1. Albert ML, Kim JI, Birge RB 2000. αvβ5 integrin recruits the CrkII–Dock180–rac1 complex for phagocytosis of apoptotic cells. Nat Cell Biol 2: 899–905 - PubMed
    1. Armstrong A, Ravichandran KS 2011. Phosphatidylserine receptors: What is the new RAGE? EMBO Rep 12: 287–288 - PMC - PubMed

Substances