Widely used mutants of eiger, encoding the Drosophila Tumor Necrosis factor, carry additional mutations in the NimrodC1 phagocytosis receptor

AbstractThe process of apoptosis in epithelia involves activation of caspases, delamination of cells, and degradation of cellular components. Corpses and cellular debris are then rapidly cleared from the tissue by phagocytic blood cells. In studies of the Drosophila TNF, Eiger (Egr) and cell death in wing imaginal discs, the epithelial primordia of fly wings, we noticed that dying cells persisted longer in egr3 mutant wing discs than in wild type discs, raising the possibility that their phagocytic engulfment by hemocytes was impaired. Further investigation revealed that lymph glands and circulating hemocytes from egr3 mutant larvae were completely devoid of NimC1 staining, a marker of phagocytic hemocytes. Genome sequencing uncovered mutations in the NimC1 coding region that are predicted to truncate the NimC1 protein before its transmembrane domain, and provide an explanation for the lack of NimC staining. The work that we report here demonstrates the presence of these NimC1 mutations in the widely used egr3 mutant, its sister allele, egr1, and its parental strain, Regg1GS9830. As the egr3 and egr1 alleles have been used in numerous studies of immunity and cell death, it may be advisable to re-evaluate their associated phenotypes.

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Widely Used Mutants of eiger, Encoding the Drosophila Tumor Necrosis Factor, Carry Additional Mutations in the NimrodC1 Phagocytosis Receptor

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401800 ◽

2020 ◽

Vol 10 (12) ◽

pp. 4707-4712

Author(s):

Albana Kodra ◽

Claire de la Cova ◽

Abigail R. Gerhold ◽

Laura A. Johnston

Keyword(s):

Cell Death ◽

Transmembrane Domain ◽

Coding Region ◽

Lymph Glands ◽

Link Type ◽

Cellular Debris ◽

Wing Imaginal Discs ◽

Wing Discs ◽

Dying Cells ◽

Cellular Components

The process of apoptosis in epithelia involves activation of caspases, delamination of cells, and degradation of cellular components. Corpses and cellular debris are then rapidly cleared from the tissue by phagocytic blood cells. In studies of the Drosophila TNF, Eiger (Egr) and cell death in wing imaginal discs, the epithelial primordia of fly wings, we noticed that dying cells appeared to transiently accumulate in egr3 mutant wing discs, raising the possibility that their phagocytic engulfment by hemocytes was impaired. Further investigation revealed that lymph glands and circulating hemocytes from egr3 mutant larvae were completely devoid of NimC1 staining, a marker of phagocytic hemocytes. Genome sequencing uncovered mutations in the NimC1 coding region that are predicted to truncate the NimC1 protein before its transmembrane domain, and provide an explanation for the lack of NimC staining. The work that we report here demonstrates the presence of these NimC1 mutations in the widely used egr3 mutant, its sister allele, egr1, and its parental strain, Regg1GS9830. As the egr3 and egr1 alleles have been used in numerous studies of immunity and cell death, it may be advisable to re-evaluate their associated phenotypes.

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Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

eLife ◽

10.7554/elife.01004 ◽

2013 ◽

Vol 2 ◽

Cited By ~ 72

Author(s):

Ainhoa Pérez-Garijo ◽

Yaron Fuchs ◽

Hermann Steller

Keyword(s):

Cell Death ◽

Local Environment ◽

Wing Disc ◽

Follicle Cells ◽

Apoptotic Cells ◽

Jnk Pathway ◽

Tnf Α ◽

Induced Apoptosis ◽

Dying Cells ◽

Necrosis Factor

Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions.

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Efferocytosis: An Interface between Apoptosis and Pathophysiology

10.5772/intechopen.97819 ◽

2021 ◽

Author(s):

Bichandarkoil Jayaram Pratima ◽

Namasivayam Nalini

Keyword(s):

Cell Death ◽

Dendritic Cells ◽

Immune System ◽

Large Family ◽

Pathogen Invasion ◽

Molecular Pattern ◽

Cellular Debris ◽

Established Cell ◽

Dying Cells ◽

Shed Light

Several cell death modes, each with a unique feature and mode of inducing cell death have been established. Cell death occurring under physiological conditions is primarily caused by apoptosis, which is a non-inflammatory or silent process, whereas necroptosis or pyroptosis is triggered by pathogen invasion, which stimulates the immune system and induces inflammation. In physiology, clearing dead cells and associated cellular debris is necessary since billions of cells die during mammalian embryogenesis and every day in adult organisms. For degradation, dead cells produced by apoptosis are quickly engulfed by macrophages. This chapter will present a description of the phagocytosis of dead and dying cells, by a process known as efferocytosis. Macrophages and, to a lesser degree, other ‘professional’ phagocytes (such as monocytes and dendritic cells) and ‘non-professional’ phagocytes, such as epithelial cells, conduct efferocytosis. Recent discoveries have shed light on this mechanism and how it works to preserve homeostasis of tissue, repair of tissue and health of the organism. Caspases are a large family of proteases of cysteine acting in cascades. A cascade leading to activation of caspase 3 mediates apoptosis and is responsible for killing cells, hiring macrophages, and presenting a “eat me” signal(s). If macrophages do not effectively engulf apoptotic cells, they undergo secondary necrosis and release intracellular materials that reflect a molecular pattern associated with injury, which can lead to autoimmune diseases. Here, the processes of efferocytosis are illustrated and the pathophysiological effects that which occur when this phase is abrogated are highlighted.

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Tumor necrosis factor (TNF) biology and cell death

Frontiers in Bioscience ◽

10.2741/2881 ◽

2008 ◽

Vol 13 (13) ◽

pp. 2736 ◽

Cited By ~ 41

Author(s):

Loris Bertazza

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Necrosis Factor

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PP2Acα promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNFα production

Cell Death and Differentiation ◽

10.1038/s41418-021-00780-5 ◽

2021 ◽

Author(s):

Yan Liang ◽

Xiaoli Sun ◽

Mingjie Wang ◽

Qingmiao Lu ◽

Mengru Gu ◽

...

Keyword(s):

Cell Death ◽

Tubular Cell ◽

Kidney Fibrosis ◽

Tubular Cells ◽

Ureter Obstruction ◽

Underlying Mechanisms ◽

Factor Α ◽

Rap1 Activation ◽

Necrosis Factor ◽

Macrophage Accumulation

AbstractMacrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα−/− macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.

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Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells

Cell Death and Disease ◽

10.1038/s41419-021-03613-y ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Hironari Nishizawa ◽

Mitsuyo Matsumoto ◽

Guan Chen ◽

Yusho Ishii ◽

Keisuke Tada ◽

...

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Lipid Peroxide ◽

Nih3t3 Cells ◽

Regulated Cell Death ◽

Primary Mouse ◽

Ischemic Diseases ◽

A Chain ◽

Dying Cells

AbstractFerroptosis is a regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

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Autonomous and non-autonomous roles of DNase II during cell death in C. elegans embryos

Bioscience Reports ◽

10.1042/bsr20150055 ◽

2015 ◽

Vol 35 (3) ◽

Cited By ~ 2

Author(s):

Hsiang Yu ◽

Huey-Jen Lai ◽

Tai-Wei Lin ◽

Szecheng J. Lo

Keyword(s):

Cell Death ◽

Caenorhabditis Elegans ◽

Fluorescence Probes ◽

Dna Fragments ◽

Dnase Ii ◽

C Elegans ◽

Dying Cells

The method of ToLFP (topoisomerase labelled fluorescence probes) is useful for detecting the DNA fragments generated by DNase II in Caenorhabditis elegans embryos. It reveals ~70% ToLFP signals in dying cells and 30% in engulfing cells during embryogenesis.

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