Phagocytosis in Human and C.elegans: History
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Subjects: Biology
Contributor:
Zsolt Dr. Farkas
,
Szilvia Lukácsi

Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence. In this review, we compare elements of phagocytosis in mammals and the nematode Caenorhabditis elegans. Initial recognition of infection requires different mechanisms. In mammals, pattern recognition receptors bind pathogens directly, whereas activation of the innate immune response in the nematode rather relies on the detection of cellular damage. In contrast, molecules involved in efferocytosis—the engulfment and elimination of dying cells and cell debris—are highly conserved between the two species. Therefore, C. elegans is a powerful model to research mechanisms of the phagocytic machinery. Finally, we show that both mammalian and worm studies help to understand how the two phagocytic functions are interconnected: emerging data suggest the activation of innate immunity as a consequence of defective apoptotic cell clearance. 

  • endocytosis
  • phagocytosis
  • apoptosis
  • efferocytosis
  • pattern recognition receptors
  • innate immunity
  • Caenorhabditis elegans

1. Forms of Endocytosis

Various portals provide regulated entry into the cells, some of these mechanisms are constitutive, while others are based on receptor-mediated interactions. Macromolecules can enter the cell, enclosed into membrane-bound carriers, during the process of endocytosis. The known mechanisms of endocytosis differ in the mode of uptake and the intracellular pathway of the internalized cargo. These mechanisms include macropinocytosis, phagocytosis, clathrin-mediated and clathrin-independent endocytosis (Figure 1A) [1]. After antigen uptake, the newly formed phagosome undergoes fusion events with various cytosolic organelles resulting in phagosome maturation. This is brought forward by the fusion with vesicles from the endosomal system, which is controlled by the Rab family of small GTPases[2]. The members of this family show a characteristic distribution, therefore they are often used as markers for the different stages of endosome maturation (Figure 1B).
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Figure 1. Forms of particle uptake and the endocytic routes. (A) The endocytic routes involve phagocytosis, macropinocytosis, clathrin mediated and clathrin independent endocytosis. (B) The fate of internalized particles is shown in the case of clathrin dependent endocytosis. Vesicles scissed from the plasma membrane quickly lose their clathrin coating and fuse with early endosomes (black arrows). Early endosomes transition into late endosomes, and in time, to lysosomes (red arrows). The recycling of receptors can occur via a short loop (green arrows), directly from early endosomes or through a long loop across the perinuclear recycling compartment (PNRC) and recycling endosomes (dark green arrows). The small GTPase Rab proteins characteristic for each stage are also indicated.

2. Phagocytosis of Apoptotic Cells

2.1. Apoptotic Engulfment in Mammals

The efficient clearance of senescent and dying cells during ontogenesis and aging is crucial for the maintenance of tissue homeostasis. The phagocytosis of apoptotic cells, termed efferocytosis, is considered to be immunologically silent or even immune-suppressive, with tissue-resident macrophages releasing anti-inflammatory mediators and dendritic cells inducing the differentiation of tolerogenic T cells after the uptake of apoptotic cells [3][4][5].
Although cells undergoing apoptosis retain an intact plasma membrane, there are changes in the phospholipid composition in the outer leaflet that work as an “eat me” signal for phagocytes. The most well-known indicator of apoptosis is the exposure of phosphatidylserine (PtdSer) on the cell surface [6]. In healthy cells, this phospholipid is actively kept in the inner leaflet by lipid transporters called flippases [7]. The caspases present during apoptosis both disrupt the function of flippases maintaining the asymmetrical distribution of PtdSer and activate scramblase enzymes that catalyse the reverse translocation of this molecule [8][9].
PtdSer is either directly recognised or is bound to receptors on phagocytes through soluble bridging molecules (Figure 2, Table 1). A PtdSer receptor (PSR) was first described by Fadok et al. using a monoclonal antibody (mAb217) that bound to the surface of macrophages and inhibited the uptake of apoptotic bodies [10]. However, subsequent experiments trying to identify this receptor produced some contradictory data [11]. The protein encoded by the psr gene, later named JMJD6 (Jumonji domain-containing protein 6), was shown to be located in the nucleus, having an important function in embryonic development with a histone demethylase activity [12][13]. Thus, it is possible that the surface molecule responsible for the binding of apoptotic bodies is not identical to the product of the suspected evolutionarily conserved psr-1 gene.
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Figure 2. Recognition and engulfment of apoptotic cells in mammalian phagocytes and C. elegans. The evolutionarily conserved CED-1/CED-6/DYN-1 (corresponding to human SCARF-1/GULP/Dynamin) and CED-2/CED-5/CED-12/CED-10 (in human: CrkII/Dock180/ELMO/Rac1) pathways are present in both C. elegans and mammals with the same functions in the clearance of apoptotic cells (orthologous molecules are indicated with the same colours). In mammals, however, a higher diversity can be observed in the recognition of apoptotic bodies, including the families of TIM and TAM proteins, complement and scavenger receptors.
Table 1. Molecules involved in the phagocytosis of apoptotic cells in human and C. elegans.
Human Protein Function C. elegans Protein
ATP8A2 P4-type ATPase/flippase TAT-1
XKR8 scramblase CED-8
SCARF1, MEGF10 and 11, LRP1 (CD91), Jedi-1 phagocytic receptor CED-1
GULP adaptor CED-6
NME1 nucleoside diphosphate kinase NDK-1
Dynamin large GTPase DYN-1
ABCA1 and ABCA7 ABC transporter CED-7
JMJD6 (PSR?) receptor PSR-1
FZD1 and 7 (Frizzled class receptor 1 and 7) receptor MOM-5
integrin α/β chain receptor INA-1/PAT-3
SRC non-receptor tyrosine kinase SRC-1
CrkII adaptor CED-2
ELMO adaptor CED-12
Dock180 Rac GEF CED-5
Rac1 Rho family GTPase CED-10
MFG-E8 bridging between PtdSer and integrins -
TIM1, 3, 4 PtdSer receptor -
Protein S, GAS6 bridging between PtdSer and TAM receptors (MER, AXL, TYRO3) -
The receptors of the TIM family (T cell immunoglobulin- and mucin-domain-containing molecule) mediate the recognition and/or uptake of apoptotic bodies in various cell types by directly binding PtdSer. All three human TIM proteins (TIM1, -3, -4) have been proven to bind PtdSer, but the internalization of particles can be cell type-specific. TIM1 functions on Th2-cells as a costimulatory molecule [14] and it is upregulated in kidney epithelial cells after injury, allowing the engulfment of apoptotic bodies for tissue recovery [15]. TIM3 is expressed on Th1 cells and dendritic cells in humans, but the internalization of PtdSer containing apoptotic bodies was only observed in myeloid cells [16][17][18]. Presumably, the most efficient apoptotic cell receptor of this family is TIM4 that is expressed on dendritic cells and various tissue-resident macrophages, like peritoneal or liver Kupffer cells, providing clearance throughout the body [19][20][21].
The indirect binding of PtdSer can happen through the bridging molecules Protein S and GAS6 (growth-arrest-specific 6) and their receptors, the tyrosine kinase TAMs (Tyro3, Axl, Mer) [22]. Protein S is synthetised mostly in liver hepatocytes and activates Tyro3 and Mer, but not Axl, whereas GAS6 acts as an agonist for all three TAM receptors [23]. The TAM receptors are expressed in both macrophages and dendritic cells, but Seitz et al. showed that DCs mainly rely on the functions of Axl and Tyro3, whereas macrophages use all three [24]. The signalling through TAMs contributes to tissue homeostasis via the inhibition of inflammatory responses in myeloid cells [25][26].
Another group of soluble PtdSer-recognizing molecules includes MFG-E8 (milk fat globule-EGF factor 8 or lactadherin) and thrombospondin, which contain RGD motifs, thus connecting apoptotic cells to the integrins αvβ3 and αvβ5 [27][28]. Both integrins were shown to cooperate with the scavenger receptor CD36 in the uptake of apoptotic cells [29][30]. The binding of apoptotic cells through these integrins initiates the phosphorylation of FAK and the recruitment of p130Cas (Crk-associated SRC substrate), which connects to the evolutionary conserved CrkII–Dock180-ELMO-Rac1 pathway mediating the engulfment of the particles through actin polymerisation and phagocytic cup formation [31][32][33]. Other scavenger receptors are also known to participate in the elimination of apoptotic cells, the specific ligands and functions of this receptor family are detailed in Section 4.1 of the original article.
The complement system also participates in the opsonization, recognition and elimination of apoptotic cells. The complement components C1q and MBL bind apoptotic and necrotic cells, enhancing their uptake by phagocytes and in the presence of serum, activating the classical and lectin pathway [34][35][36]. The activation of the alternative pathway by apoptotic cells was also proved by several studies, resulting in the deposition of C3 fragments and phagocytosis by the complement receptors CR1, CR3, CR4 and CRIg [37][38][39]. Opsonization with complement facilitates the quick and effective clearance of apoptotic cells without an inflammatory response, which is further supported by the immunosuppressive qualities of C1q [40][41].

2.2. Apoptotic Engulfment and Clearance in C. elegans

Programmed cell death can be divided into three phases: the first is the specification of the cell destined to die, and the second is the killing phase, where the apoptotic pathway is activated and lastly the execution of cell death and dismantling. The last phase also includes the elimination of apoptotic bodies, where a specialized or neighbouring cell engulfs and removes the debris of the dying cell. The conserved genes involved in the core apoptotic pathway were first identified in C. elegans, for which the Nobel prize for Medicine was awarded to Sydney Brenner, John E. Sulston, and H. Robert Horvitz in 2002 [42][43].
Phagocytosis of apoptotic corpses involves conserved pathways in the nematode (Table 2). The worm does not possess dedicated macrophages; instead, the neighbouring cells provide the phagocytic function. Similar to other organisms, the well-conserved PtdSer acts as the main signal of cell death or “eat-me” signal. The exposure of PtdSer in the worm during apoptosis is linked to the amino phospholipid translocase TAT-1 (Transbilayer Amphipath Transporter, ortholog of human flippase, ATPase phospholipid transporting 8A2, ATP8A2) and CED-8 (CEll Death abnormality 8, ortholog of human scramblase XKR8) function. In a living cell translocases actively transport PtdSer from the outer to the inner leaflet of the plasma membrane, but in an apoptotic cell, the inactivation of translocases and the activation of scramblases results in PtdSer accumulation on the cell surface [44]. After the recognition of an apoptotic cell, the activated receptors stimulate the extension of the engulfing cell’s membrane and the rearrangement of the actin cytoskeleton. Consequently, the phagocytic cell develops pseudopods around the dying cell. Just as the pseudopods fuse, the newly formed phagosome separates from the plasma membrane [45].
Two main, partly overlapping and conserved signalling pathways control the engulfment of apoptotic cells in C. elegans [46]. One contains the phagocytic receptor CED-1 (human SCARF-1), the adaptor CED-6 (GULP), the ABC transporter CED-7 (ABCA) and the large GTPase DYN-1 (Dynamin2). The second path entails the CED-2 (CrkII), CED-5 (Dock180), CED-10 (Rac1), CED-12 (ELMO) proteins, the latter being the counterpart of the human Rac signalling. These two pathways partly converge at CED-10 involved in actin polymerisation, regulating the required cytoskeleton rearrangement for engulfment [47][48].
The first pathway is triggered by the phagocytic transmembrane receptor CED-1, which only appears on the surface of the engulfing cell. After ligand recognition, the amount of CED-1 increases in the engulfing cell’s plasma membrane that is in contact with the neighbouring dead cell, initiating the formation of the phagocytic cup. The PtdSer driven activation of CED-1 triggers the subsequent members of the signalling cascade, resulting in the growth of pseudopods [49]. CED-7 has a dual role to mediate the eat-me signal, it is expressed in both the engulfed and the engulfing cell: CED-7 assists in the exposure of PtdSer and also helps CED-1 to capture the PtdSer signal [50]. Then the activated CED-1 signal is transmitted by CED-6, partly activating CED-10, but mostly triggers through DYN-1 that regulates the extension of the engulfing cell membrane [47].
DYN-1 is a large GTPase that has multiple roles related to membrane trafficking. During engulfment, the phagocytic cup is transiently enriched in DYN-1 that provides the surplus of membrane necessary for pseudopod extension by helping the recruitment of early endosomes and their fusion with the cell membrane [51]. Furthermore, it also mediates the last event in the engulfment process, namely the fission of phagosomes from the plasma membrane [52]. For these functions, DYN-1 requires high amounts of GTP, which is provided by NDK-1 (Nucleoside Diphosphate Kinase-1, ortholog of human NME1) [53]. It is important to note that both DYN-1 and NDK-1 are detected on the surface of early phagosomes, indicating that they also have roles in the early steps of phagosome maturation [51][53][54].
The second pathway has an equally important role in the engulfing process: next to the membrane extension detailed above, the rearrangement of actin cytoskeleton is also crucial for the internalization of apoptotic cells. The components of this pathway regulate CED-10 activation [55]. The pathway is triggered by the recognition of PtdSer by three different receptors: integrins, PSR-1 and MOM-5. The core of this pathway is the CED-2/CED-5/CED-12 trio, which complex acts as the guanine nucleotide exchange factor (GEF) of CED-10. The first possible route to trigger this pathway is through the integrin consisting of two subunits: INA-1 (integrin alpha-1) and PAT-3 (Paralysed Arrest at Two-fold, beta subunit) [56][57]. In this case, CED-2 connects to the integrin receptor through SRC-1 (SRC oncogene related) and recruits the other two members of its complex [56]. The other alpha subunit, PAT-2, might also have a role in recognising PtdSer, but the results published about the exact role of the PAT-2/PAT-3 heterodimer receptor in phagocytosis is controversial [58][59]. The next receptor that has an influence on this pathway is PSR-1 (ortholog of human PSR, phosphatidyl serine receptor). CED-12 directly connects to this receptor and recruits the other two members of its complex upon activation [57]. Besides the above-mentioned two receptors, the Frizzled homolog MOM-5 (More Of MS 5) connects the Wnt signalling to the engulfment process, which also acts through the CED-2/CED-5/CED-12 complex [60].
Recently, a third pathway has been identified, revealing the important role of RAB-35 in the early steps of apoptotic cell phagocytosis. RAB-35 is a multifunctional GTPase that plays important roles in phagocytosis, cytokinesis, apico-basal polarity, cell migration, neurite outgrowth, immune synapse, exosome release and pathogen hijacking [61]. During phagocytosis, RAB-35 localizes at the developing pseudopods, and later on early phagosomes, suggesting a function in early phagocytic events [62]. The Zhou laboratory identified a novel role for RAB-35: rab-35 mutants show a delay in apoptotic cell recognition, also rab-35 mutant phenotypes are enhanced in both ced-1 and ced-5 mutant backgrounds, which is further worsened in ced-1, rab-35, ced-5 triple mutants. As a conclusion, rab-35 functions in a third pathway in parallel to the ced-2/-5/-10/-12 and ced-1/-6/-7 pathways, and further genetic epistasis analysis indicates that rab-35 function is also linked to the integrin pathway [62].

2.3. The Interconnection of Innate Immunity with Apoptotic Cell Clearance and the Nervous System

Phagocytes perform a dual role in host defence as they are both responsible for removing apoptotic debris and initiating an innate immune response against pathogens. Despite its importance, the connection between these two functions is poorly understood. Recently it was shown in C. elegans that mutations in the genes involved in apoptotic cell clearance make them more resistant to the pathogenic bacteria Pseudomonas aeruginosa and Salmonella typhimurium [63]. The mutant worms showed an upregulation of the innate immune response genes, even in the absence of bacterial pathogens, and this response was actively regulated by the apoptotic cell clearance defects through the PMK-1 and MPK-1 pathways [63].
Similar observations were documented in mammals: inefficient removal of dead cells activates the innate immune system [64]. In DNaseII knockout mice, the DNA of apoptotic cells is not entirely degraded in lysosomes, which leads to the induction of an immune response and the development of chronic arthritis and anaemia [64]. In line with these data, the production of antibacterial peptides was observed both in C. elegans and Drosophila if apoptotic germ cells lacked DNaseII [65][66]. As there are some controversial data [67], further investigation is needed to precisely determine the relationship between the innate immune response and apoptotic cell clearance.
Interestingly, recent studies also suggest a neurological connection to immunity, as worms were proven to be able to avoid pathogen attacks through sensing microbes via their nervous system. Multiple sensory neurons and GPCRs are involved in the detection of specific molecules and the local fluctuations of oxygen and carbon dioxide levels generated by bacterial metabolism (reviewed in [68]). Thus, it is thought that the nervous system can regulate immunity in the nematode, in line with similar findings observed earlier in mammals [69][70][71]. C. elegans has only 302 neurons with detailed functional and morphological characterization available, and together with the knowledge of the entire synaptic wiring diagram, it can provide useful insights into the research of vertebrate neuroimmunology.

This entry is adapted from the peer-reviewed paper 10.3390/ijms22168934

References

  1. Walpole, G.F.W.; Grinstein, S. Endocytosis and the internalization of pathogenic organisms: Focus on phosphoinositides. F1000Research 2020, 9, 1–17.
  2. Cummings, R.J.; Barbet, G.; Bongers, G.; Hartmann, B.M.; Gettler, K.; Muniz, L.; Furtado, G.C.; Cho, J.; Lira, S.A.; Blander, J.M. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 2016, 539, 565–569.
  3. Quintana, J.A.; García-Silva, S.; Mazariegos, M.; González de la Aleja, A.; Nicolás-Ávila, J.A.; Walter, W.; Adrover, J.M.; Crainiciuc, G.; Kuchroo, V.K.; Rothlin, C.V.; et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J. Exp. Med. 2017, 214, 1281–1296.
  4. Roberts, A.W.; Lee, B.L.; Deguine, J.; John, S.; Shlomchik, M.J.; Barton, G.M. Tissue-Resident Macrophages Are Locally Programmed for Silent Clearance of Apoptotic Cells. Immunity 2017, 47, 913–927.e6.
  5. Fadok, V.A.; Voelker, D.R.; Campbell, P.A.; Cohen, J.J.; Bratton, D.L.; Henson, P.M. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 1992, 148, 2207–2216.
  6. Andersen, J.P.; Vestergaard, A.L.; Mikkelsen, S.A.; Mogensen, L.S.; Chalat, M.; Molday, R.S. P4-ATPases as Phospholipid Flippases-Structure, Function, and Enigmas. Front. Physiol. 2016, 7, 275.
  7. Segawa, K.; Kurata, S.; Yanagihashi, Y.; Brummelkamp, T.R.; Matsuda, F.; Nagata, S. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 2014, 344, 1164–1168.
  8. Suzuki, J.; Denning, D.P.; Imanishi, E.; Horvitz, H.R.; Nagata, S. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 2013, 341, 403–406.
  9. Fadok, V.A.; Bratton, D.L.; Rose, D.M.; Pearson, A.; Ezekewitz, R.A.; Henson, P.M. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 2000, 405, 85–90.
  10. Williamson, P.; Schlegel, R.A. Hide and seek: The secret identity of the phosphatidylserine receptor. J. Biol. 2004, 3, 1–4.
  11. Klose, R.J.; Kallin, E.M.; Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nat. Rev. Genet. 2006, 7, 715–727.
  12. Böse, J.; Gruber, A.D.; Helming, L.; Schiebe, S.; Wegener, I.; Hafner, M.; Beales, M.; Köntgen, F.; Lengeling, A. The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J. Biol. 2004, 3, 715–727.
  13. Umetsu, S.E.; Lee, W.-L.; McIntire, J.J.; Downey, L.; Sanjanwala, B.; Akbari, O.; Berry, G.J.; Nagumo, H.; Freeman, G.J.; Umetsu, D.T.; et al. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nat. Immunol. 2005, 6, 447–454.
  14. Ichimura, T.; Asseldonk, E.J.P.V.; Humphreys, B.D.; Gunaratnam, L.; Duffield, J.S.; Bonventre, J.V. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J. Clin. Invest. 2008, 118, 1657–1668.
  15. Monney, L.; Sabatos, C.A.; Gaglia, J.L.; Ryu, A.; Waldner, H.; Chernova, T.; Manning, S.; Greenfield, E.A.; Coyle, A.J.; Sobel, R.A.; et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002, 415, 536–541.
  16. Anderson, A.C.; Anderson, D.E.; Bregoli, L.; Hastings, W.D.; Kassam, N.; Lei, C.; Chandwaskar, R.; Karman, J.; Su, E.W.; Hirashima, M.; et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 2007, 318, 1141–1143.
  17. de Mingo Pulido, Á.; Gardner, A.; Hiebler, S.; Soliman, H.; Rugo, H.S.; Krummel, M.F.; Coussens, L.M.; Ruffell, B. TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer. Cancer Cell 2018, 33, 60–74.e6.
  18. Kobayashi, N.; Karisola, P.; Peña-Cruz, V.; Dorfman, D.M.; Jinushi, M.; Umetsu, S.E.; Butte, M.J.; Nagumo, H.; Chernova, I.; Zhu, B.; et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 2007, 27, 927–940.
  19. Miyanishi, M.; Tada, K.; Koike, M.; Uchiyama, Y.; Kitamura, T.; Nagata, S. Identification of Tim4 as a phosphatidylserine receptor. Nature 2007, 450, 435–439.
  20. Lemke, G. How macrophages deal with death. Nat. Rev. Immunol. 2019, 19, 539–549.
  21. Nagata, S. Apoptosis and Clearance of Apoptotic Cells. Annu. Rev. Immunol. 2018, 36, 489–517.
  22. Lew, E.D.; Oh, J.; Burrola, P.G.; Lax, I.; Zagórska, A.; Través, P.G.; Schlessinger, J.; Lemke, G. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. Elife 2014, 3, 1–23.
  23. Seitz, H.M.; Camenisch, T.D.; Lemke, G.; Earp, H.S.; Matsushima, G.K. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J. Immunol. 2007, 178, 5635–5642.
  24. Rothlin, C.V.; Ghosh, S.; Zuniga, E.I.; Oldstone, M.B.A.; Lemke, G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007, 131, 1124–1136.
  25. van der Meer, J.H.M.; van der Poll, T.; van ’t Veer, C. TAM receptors, Gas6, and protein S: Roles in inflammation and hemostasis. Blood 2014, 123, 2460–2469.
  26. Hanayama, R.; Tanaka, M.; Miwa, K.; Shinohara, A.; Iwamatsu, A.; Nagata, S. Identification of a factor that links apoptotic cells to phagocytes. Nature 2002, 417, 182–187.
  27. Stern, M.; Savill, J.; Haslett, C. Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis. Mediation by alpha v beta 3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am. J. Pathol. 1996, 149, 911–921.
  28. Albert, M.L.; Pearce, S.F.; Francisco, L.M.; Sauter, B.; Roy, P.; Silverstein, R.L.; Bhardwaj, N. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 1998, 188, 1359–1368.
  29. Savill, J.; Hogg, N.; Ren, Y.; Haslett, C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 1992, 90, 1513–1522.
  30. Albert, M.L.; Kim, J.I.; Birge, R.B. alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nat. Cell Biol. 2000, 2, 899–905.
  31. Gumienny, T.L.; Brugnera, E.; Tosello-Trampont, A.C.; Kinchen, J.M.; Haney, L.B.; Nishiwaki, K.; Walk, S.F.; Nemergut, M.E.; Macara, I.G.; Francis, R.; et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 2001, 107, 27–41.
  32. Shah, P.P.; Fong, M.Y.; Kakar, S.S. PTTG induces EMT through integrin αVβ3-focal adhesion kinase signaling in lung cancer cells. Oncogene 2012, 31, 3124–3135.
  33. Liang, Y.Y.; Arnold, T.; Michlmayr, A.; Rainprecht, D.; Perticevic, B.; Spittler, A.; Oehler, R. Serum-dependent processing of late apoptotic cells for enhanced efferocytosis. Cell Death Dis. 2014, 5, e1264.
  34. Nauta, A.J.; Castellano, G.; Xu, W.; Woltman, A.M.; Borrias, M.C.; Daha, M.R.; van Kooten, C.; Roos, A. Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells. J. Immunol. 2004, 173, 3044–3050.
  35. Fraser, D.A.; Laust, A.K.; Nelson, E.L.; Tenner, A.J. C1q differentially modulates phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells. J. Immunol. 2009, 183, 6175–6185.
  36. Takizawa, F.; Tsuji, S.; Nagasawa, S. Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells. FEBS Lett. 1996, 397, 269–272.
  37. Matsui, H.; Tsuji, S.; Nishimura, H.; Nagasawa, S. Activation of the alternative pathway of complement by apoptotic Jurkat cells. FEBS Lett. 1994, 351, 419–422.
  38. Mevorach, D.; Mascarenhas, J.O.; Gershov, D.; Elkon, K.B. Complement-dependent clearance of apoptotic cells by human macrophages. J. Exp. Med. 1998, 188, 2313–2320.
  39. Benoit, M.E.; Clarke, E.V.; Morgado, P.; Fraser, D.A.; Tenner, A.J. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J. Immunol. 2012, 188, 5682–5693.
  40. Fraser, D.A.; Arora, M.; Bohlson, S.S.; Lozano, E.; Tenner, A.J. Generation of inhibitory NFkappaB complexes and phosphorylated cAMP response element-binding protein correlates with the anti-inflammatory activity of complement protein C1q in human monocytes. J. Biol. Chem. 2007, 282, 7360–7367.
  41. Conradt, B.; Xue, D. Programmed Cell Death; WormBook: Pasadena, CA, USA, 2005; pp. 1–13.
  42. Conradt, B.; Wu, Y.-C.; Xue, D. Programmed Cell Death During Caenorhabditis elegans Development. Genetics 2016, 203, 1533–1562.
  43. Bratton, D.L.; Fadok, V.A.; Richter, D.A.; Kailey, J.M.; Guthrie, L.A.; Henson, P.M. Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J. Biol. Chem. 1997, 272, 26159–26165.
  44. Lu, N.; Zhou, Z. Membrane trafficking and phagosome maturation during the clearance of apoptotic cells. Int. Rev. Cell Mol. Biol. 2012, 293, 269–309.
  45. Mangahas, P.M.; Zhou, Z. Clearance of apoptotic cells in Caenorhabditis elegans. Semin. Cell Dev. Biol. 2005, 16, 295–306.
  46. Kinchen, J.M.; Cabello, J.; Klingele, D.; Wong, K.; Feichtinger, R.; Schnabel, H.; Schnabel, R.; Hengartner, M.O. Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature 2005, 434, 93–99.
  47. Shen, Q.; He, B.; Lu, N.; Conradt, B.; Grant, B.D.; Zhou, Z. Phagocytic receptor signaling regulates clathrin and epsin-mediated cytoskeletal remodeling during apoptotic cell engulfment in C. elegans. Development 2013, 140, 3230–3243.
  48. Zhou, Z.; Hartwieg, E.; Horvitz, H.R. CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 2001, 104, 43–56.
  49. Venegas, V.; Zhou, Z. Two alternative mechanisms that regulate the presentation of apoptotic cell engulfment signal in Caenorhabditis elegans. Mol. Biol. Cell 2007, 18, 3180–3192.
  50. Yu, X.; Odera, S.; Chuang, C.-H.; Lu, N.; Zhou, Z. C. elegans Dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells. Dev. Cell 2006, 10, 743–757.
  51. Schmid, S.L.; Frolov, V.A. Dynamin: Functional design of a membrane fission catalyst. Annu. Rev. Cell Dev. Biol. 2011, 27, 79–105.
  52. Farkas, Z.; Petric, M.; Liu, X.; Herit, F.; Rajnavölgyi, É.; Szondy, Z.; Budai, Z.; Orbán, T.I.; Sándor, S.; Mehta, A.; et al. The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/Dynamin. FASEB J. 2019, 33, 11606–11614.
  53. Yu, X.; Lu, N.; Zhou, Z. Phagocytic receptor CED-1 initiates a signaling pathway for degrading engulfed apoptotic cells. PLoS Biol. 2008, 6, e61.
  54. Reddien, P.W.; Horvitz, H.R. The engulfment process of programmed cell death in Caenorhabditis elegans. Annu. Rev. Cell Dev. Biol. 2004, 20, 193–221.
  55. Hsu, T.-Y.; Wu, Y.-C. Engulfment of apoptotic cells in C. elegans is mediated by integrin alpha/SRC signaling. Curr. Biol. 2010, 20, 477–486.
  56. Wang, X.; Wu, Y.-C.; Fadok, V.A.; Lee, M.-C.; Gengyo-Ando, K.; Cheng, L.-C.; Ledwich, D.; Hsu, P.-K.; Chen, J.-Y.; Chou, B.-K.; et al. Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12. Science 2003, 302, 1563–1566.
  57. Hsieh, H.-H.; Hsu, T.-Y.; Jiang, H.-S.; Wu, Y.-C. Integrin α PAT-2/CDC-42 signaling is required for muscle-mediated clearance of apoptotic cells in Caenorhabditis elegans. PLoS Genet. 2012, 8, e1002663.
  58. Neukomm, L.J.; Zeng, S.; Frei, A.P.; Huegli, P.A.; Hengartner, M.O. Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans. Cell Death Differ. 2014, 21, 845–853.
  59. Cabello, J.; Neukomm, L.J.; Günesdogan, U.; Burkart, K.; Charette, S.J.; Lochnit, G.; Hengartner, M.O.; Schnabel, R. The Wnt pathway controls cell death engulfment, spindle orientation, and migration through CED-10/Rac. PLoS Biol. 2010, 8, e1000297.
  60. Klinkert, K.; Echard, A. Rab35 GTPase: A Central Regulator of Phosphoinositides and F-actin in Endocytic Recycling and Beyond. Traffic 2016, 17, 1063–1077.
  61. Haley, R.; Wang, Y.; Zhou, Z. The small GTPase RAB-35 defines a third pathway that is required for the recognition and degradation of apoptotic cells. PLoS Genet. 2018, 14, e1007558.
  62. Wan, J.; Yuan, L.; Jing, H.; Zheng, Q.; Xiao, H. Defective apoptotic cell clearance activates innate immune response to protect Caenorhabditis elegans against pathogenic bacteria. Virulence 2021, 12, 75–83.
  63. Kawane, K.; Ohtani, M.; Miwa, K.; Kizawa, T.; Kanbara, Y.; Yoshioka, Y.; Yoshikawa, H.; Nagata, S. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 2006, 443, 998–1002.
  64. Yu, H.; Lai, H.-J.; Lin, T.-W.; Chen, C.-S.; Lo, S.J. Loss of DNase II function in the gonad is associated with a higher expression of antimicrobial genes in Caenorhabditis elegans. Biochem. J. 2015, 470, 145–154.
  65. Mukae, N.; Yokoyama, H.; Yokokura, T.; Sakoyama, Y.; Nagata, S. Activation of the innate immunity in Drosophila by endogenous chromosomal DNA that escaped apoptotic degradation. Genes Dev. 2002, 16, 2662–2671.
  66. Seong, C.-S.; Varela-Ramirez, A.; Aguilera, R.J. DNase II deficiency impairs innate immune function in Drosophila. Cell. Immunol. 2006, 240, 5–13.
  67. Liu, Y.; Sun, J. Detection of Pathogens and Regulation of Immunity by the Caenorhabditis elegans Nervous System. MBio 2021, 12, 1–12.
  68. Sternberg, E.M. Neural regulation of innate immunity: A coordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 2006, 6, 318–328.
  69. Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 2004, 5, 575–581.
  70. Tracey, K.J. The inflammatory reflex. Nature 2002, 420, 853–859.
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