Necroptosis, pyroptosis and apoptosis: an intricate game of cell death

AbstractCell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as ‘programmed cell death’ have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies have highlighted the complex mechanisms tipping the balance between different cell fates. Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.

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A Screen for Mutations That Suppress the Phenotype of Drosophila armadillo, the β-Catenin Homolog

Genetics ◽

10.1093/genetics/155.4.1725 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1725-1740

Author(s):

Rachel T Cox ◽

Donald G McEwen ◽

Denise L Myster ◽

Robert J Duronio ◽

Joseph Loureiro ◽

...

Keyword(s):

Cell Death ◽

Cell Adhesion ◽

Programmed Cell Death ◽

Cell Survival ◽

Wnt Pathway ◽

Genetic Modifier ◽

Wnt Signaling Pathway ◽

Adherens Junction ◽

Cell Fates ◽

Wnt Signal

Abstract During development signaling pathways coordinate cell fates and regulate the choice between cell survival or programmed cell death. The well-conserved Wingless/Wnt pathway is required for many developmental decisions in all animals. One transducer of the Wingless/Wnt signal is Armadillo/β-catenin. Drosophila Armadillo not only transduces Wingless signal, but also acts in cell-cell adhesion via its role in the epithelial adherens junction. While many components of both the Wingless/Wnt signaling pathway and adherens junctions are known, both processes are complex, suggesting that unknown components influence signaling and junctions. We carried out a genetic modifier screen to identify some of these components by screening for mutations that can suppress the armadillo mutant phenotype. We identified 12 regions of the genome that have this property. From these regions and from additional candidate genes tested we identified four genes that suppress arm: dTCF, puckered, head involution defective (hid), and Dpresenilin. We further investigated the interaction with hid, a known regulator of programmed cell death. Our data suggest that Wg signaling modulates Hid activity and that Hid regulates programmed cell death in a dose-sensitive fashion.

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The role of B7 family molecules in hematologic malignancy

Blood ◽

10.1182/blood-2012-10-385591 ◽

2013 ◽

Vol 121 (5) ◽

pp. 734-744 ◽

Cited By ~ 98

Author(s):

Paul Greaves ◽

John G. Gribben

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Immune Responses ◽

Hematologic Malignancy ◽

Surface Proteins ◽

Cell Responses ◽

Inducible Costimulator ◽

Programmed Cell Death 1 ◽

B7 Family

AbstractThe B7 family consists of structurally related, cell-surface proteins that regulate immune responses by delivering costimulatory or coinhibitory signals through their ligands. Eight family members have been identified to date including CD80 (B7-1), CD86 (B7-2), CD274 (programmed cell death-1 ligand [PD-L1]), CD273 (programmed cell death-2 ligand [PD-L2]), CD275 (inducible costimulator ligand [ICOS-L]), CD276 (B7-H3), B7-H4, and B7-H6. B7 ligands are expressed on both lymphoid and nonlymphoid tissues. The importance of the B7 family in regulating immune responses is clear from their demonstrated role in the development of immunodeficiency and autoimmune diseases. Manipulation of the signals delivered by B7 ligands shows great potential in the treatment of cancers including leukemias and lymphomas and in regulating allogeneic T-cell responses after stem cell transplantation.

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Control of Programmed Cell Death During Zebrafish Embryonic Development

Recent Advances in Zebrafish Researches ◽

10.5772/intechopen.74494 ◽

2018 ◽

Cited By ~ 1

Author(s):

Nikolay Popgeorgiev ◽

Benjamin Bonneau ◽

Julien Prudent ◽

Germain Gillet

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Embryonic Development

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Post-embryonic development in the ventral cord of Caenorhabditis elegans

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1976.0084 ◽

1976 ◽

Vol 275 (938) ◽

pp. 287-297 ◽

Cited By ~ 195

Keyword(s):

Cell Death ◽

Caenorhabditis Elegans ◽

Programmed Cell Death ◽

Embryonic Development ◽

Nerve Cells ◽

Ventral Cord ◽

Larval Moult ◽

A Cell

56 nerve cells are added to the ventral cord and associated ganglia of Caenorhabditis elegans at about the time of the first larval moult. These cells are produced by the uniform division of 13 neuroblasts followed by a defined pattern of cell deaths. Comparison with the data in the previous paper suggests that there is a relationship between the ancestry of a cell and its function. The significance of programmed cell death is discussed.

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Expression of PD-L1 in Leukemic Progenitor Cells Defines NPM1 Mutated AML As a Potential Subgroup for PD1/PD-L1 Directed Immunotherapy

Blood ◽

10.1182/blood-2018-99-111458 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2734-2734

Author(s):

Jochen Greiner ◽

Vanessa Schneider ◽

Hubert Schrezenmeier ◽

Markus Wiesneth ◽

Lars Bullinger ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Immune Responses ◽

Progenitor Cells ◽

Board Of Directors ◽

Research Funding ◽

Significant Inhibition ◽

Leukemic Cells ◽

Advisory Committees ◽

Oncology Research

Abstract Clinical and preclinical data suggest that acute myeloid leukemia (AML) with mutated nucleophosmin 1(NPM1mut) may constitute an immunogenic leukemia subtype. NPM1mut AML generally correlates with a better prognosis, however the underlying mechanisms still need to be clarified. Checkpoint inhibition targeting Programmed cell death protein 1 (PD-1)/Programmed cell death 1 ligand 1 (PD-L1) has been proven to be an effective novel immunotherapeutic approach in cancer treatment including the treatment of hematological malignancies. Expression of CD34/CD38/CD274 was evaluated in 20 NPM1mut versus 20 wild-type (NPM1wt) AML patient samples via flow cytometry analyses to assess PD-L1 (CD274) expression in leukemic cells, including leukemic progenitor and stem cells (LSC). We also investigated the influence of the anti-PD-1 antibody Nivolumab® on the antigen-specific immune responses in ELISpot assays. Additionally, we assessed the effect of Nivolumab in colony forming unit (CFU) immunoassays. Many AML cases showed relevant expression of PD-L1. Bulk cells of NPM1mut AML showed a significantly higher PD-L1 expression in comparison to NPM1wtAML patients (median of 1.5%, range 0.0-8.5%, versus 0.3%, range 0.1-1.1%). Importantly, PD-L1 expression was detected at a higher level in leukemic progenitor cells (CD34+CD38-) of NPM1mut than of NPM1wtAML (median of 3.3%, range 0.0-17.2%, versus 0.3%, range 0.0-3.0%). In general, the LSC fraction showed a higher PD-L1 expression than the non-LSC fraction. CFU immunoassays showed a significant inhibition of CFU when adding T cells stimulated against various LAA. In all patient samples, effectors activated against at least one LAA were successful to decrease the colony number significantly. Immune effects increased adding Nivolumab to the CTL for several days before starting CFU immunoassays. In summary, we detected higher PD-L1 expression in NPM1mut patients, especially in the leukemic progenitor compartment. This observation further supports the hypothesis that NPM1-directed immune responses might play an important role in tumor cell rejection, which tumor cells try to escape via expression of PD-L1. Immunogenicity of neoantigens derived from NPM1mut with higher PD-L1 expression constitute promising target structures for individualized immunotherapeutic approaches. Disclosures Schrezenmeier: Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Bullinger:Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer Oncology: Research Funding. Döhner:Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria.

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Caspases in Cell Death, Inflammation, and Pyroptosis

Annual Review of Immunology ◽

10.1146/annurev-immunol-073119-095439 ◽

2020 ◽

Vol 38 (1) ◽

pp. 567-595 ◽

Cited By ~ 27

Author(s):

Sannula Kesavardhana ◽

R.K. Subbarao Malireddi ◽

Thirumala-Devi Kanneganti

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Immune Responses ◽

Cross Talk ◽

Cysteine Proteases ◽

Proteolytic Processing ◽

Innate Immune ◽

Innate Immune Responses ◽

New Research ◽

Multicellular Organisms

Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D–induced pyroptosis.

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Cell death in normal and rough eye mutants of Drosophila

Development ◽

10.1242/dev.113.3.825 ◽

1991 ◽

Vol 113 (3) ◽

pp. 825-839 ◽

Cited By ~ 27

Author(s):

T. Wolff ◽

D.F. Ready

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Compound Eye ◽

Cell Lineage ◽

Cell Fates ◽

Cone Cells ◽

A Cell ◽

Retinal Epithelium ◽

Fly Eye ◽

Dying Cells

The regular, reiterated cellular pattern of the Drosophila compound eye makes it a sensitive amplifier of defects in cell death. Quantitative and histological methods reveal a phase of cell death between 35 and 50 h of development which removes between 2 and 3 surplus cells per ommatidium. The timing of this epoch is consistent with cell death as the last fate to be specified in the progressive sequence of cell fates that build the ommatidium. An ultrastructural survey of cell death suggests dying cells in the fly eye have similarities as well as differences with standard descriptions of programmed cell death. A failure of cell death to remove surplus cells disorganizes the retinal lattice. A screen of rough eye mutants identifies two genes, roughest and echinus, required for the normal elimination of cells from the retinal epithelium. The use of an enhancer trap as a cell lineage marker shows that the cone cells, like other retinal cells, are not clonally related to each other or to their neighbors.

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Local induction of patterning and programmed cell death in the developing Drosophila retina

Development ◽

10.1242/dev.125.12.2327 ◽

1998 ◽

Vol 125 (12) ◽

pp. 2327-2335 ◽

Cited By ~ 21

Author(s):

D.T. Miller ◽

R.L. Cagan

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Egf Receptor ◽

Pigment Cells ◽

Cell Fates ◽

Adult Retina ◽

Ras Pathway ◽

Cell Ablation ◽

Cone Cells ◽

Local Cell

Local cell signaling can pattern the nervous system by directing cell fates, including programmed cell death. In the developing Drosophila retina, programmed cell death is used to remove excess cells between ommatidia. Cell ablation revealed the source and position of signals required for regulating the pattern of programmed cell death among these interommatidial cells. Two types of signals regulate this patterning event. Notch-mediated signals between interommatidial precursors result in removal of unneeded cells. Cone cells and primary pigment cells oppose this signal by supplying a ‘life’-promoting activity; evidence is provided that this signal occurs through localized activation of the EGF Receptor/Ras pathway. Together, these signals refine the highly regular pattern observed in the adult retina.

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