scholarly journals ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet mediated degeneration

2020 ◽  
Author(s):  
Sonia Muliyil ◽  
Clémence Levet ◽  
Stefan Düsterhöft ◽  
Iqbal Dulloo ◽  
Sally Cowley ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Tumour Necrosis ◽  
Later Life ◽  
Cellular Damage ◽  
Oxygen Species ◽  
Tnf Receptor ◽  
Age Related ◽  
Abnormal Accumulation ◽  
Necrosis Factor ◽  
Tnf Tumour Necrosis Factor

AbstractAnimals have evolved multiple mechanisms to protect themselves from the cumulative effects of age-related cellular damage. Here we reveal an unexpected link between the TNF (tumour necrosis factor) inflammatory pathway, triggered by the metalloprotease ADAM17/TACE, and a lipid droplet (LD)-mediated mechanism of protecting retinal cells from age related degeneration. Loss of ADAM17, TNF and the TNF receptor Grindelwald in pigmented glial cells of the Drosophila retina leads to age related degeneration of both glia and neurons, preceded by an abnormal accumulation of glial LDs. We show that the glial LDs initially buffer the cells against damage caused by neuronally generated reactive oxygen species (ROS), but that in later life the LDs dissipate, leading to the release of toxic peroxidated lipids. Finally, we demonstrate the existence of a conserved pathway in human iPS-derived microglia-like cells, which are central players in neurodegeneration. Overall, we have discovered a pathway mediated by TNF signalling acting not as a trigger of inflammation, but as a cytoprotective factor in the retina.

Host response to cytoadherence in Plasmodium falciparum

2008 ◽  
Vol 36 (2) ◽  
pp. 221-228 ◽  
Author(s):  
Srabasti J. Chakravorty ◽  
Katie R. Hughes ◽  
Alister G. Craig
Keyword(s):  
Plasmodium Falciparum ◽  
Tumour Necrosis ◽  
Host Response ◽  
Severe Disease ◽  
Signalling Pathways ◽  
Malarial Infection ◽  
Extensive Information ◽  
Adhesive Interactions ◽  
Necrosis Factor ◽  
Tnf Tumour Necrosis Factor

Cytoadherence of PRBCs (Plasmodium falciparum-infected red blood cells) to host endothelium has been associated with pathology in severe malaria, but, despite extensive information on the primary processes involved in the adhesive interactions, the mechanisms underlying the disease are poorly understood. Endothelial cells have the ability to mobilize immune and pro-adhesive responses when exposed to both PRBCs and TNF (tumour necrosis factor). In addition, there is also an up-regulation by PRBCs and TNF and a concurrent down-regulation of a range of genes involved in inflammation and cell death, by PRBCs and TNF. We propose that the balance between positive and negative regulation will contribute to endothelial pathology during malarial infection. Apposition of PRBCs has been shown by a number of groups to activate signalling pathways. This is dependent, at least in part, on the cytoadherence characteristics of the invading isolate, such that the avidity of the PRBC for the receptor on host endothelium is proportional to the level of activation of the signalling pathways. An understanding of the post-adhesive processes produced by cytoadherence may help us to understand the variable pathology seen in malaria and to design appropriate therapies to alleviate severe disease.

Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice

Nature ◽  
1994 ◽  
Vol 372 (6506) ◽  
pp. 560-563 ◽  
Author(s):  
Sharon L. Erickson ◽  
Frederic J. de Sauvage ◽  
Kristine Kikly ◽  
Karen Carver-Moore ◽  
Sharon Pitts-Meek ◽  
...  
Keyword(s):  
T Cell ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
T Cell Development ◽  
Cell Development ◽  
Tnf Receptor ◽  
Deficient Mice ◽  
Necrosis Factor

scholarly journals Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor κB to modulate tumour necrosis factor-induced apoptosis: evidence from mitochondria-targeted antioxidants

2005 ◽  
Vol 389 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Gillian HUGHES ◽  
Michael P. MURPHY ◽  
Elizabeth C. LEDGERWOOD
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Mitochondrial Matrix ◽  
Mitochondrial Ros ◽  
Induced Apoptosis ◽  
Necrosis Factor

ROS (reactive oxygen species) from mitochondrial and non-mitochondrial sources have been implicated in TNFα (tumour necrosis factor α)-mediated signalling. In the present study, a new class of specific mitochondria-targeted antioxidants were used to explore directly the role of mitochondrial ROS in TNF-induced apoptosis. MitoVit E {[2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethyl]triphenylphosphonium bromide} (vitamin E attached to a lipophilic cation that facilitates accumulation of the antioxidant in the mitochondrial matrix) enhanced TNF-induced apoptosis of U937 cells. In time course analyses, cleavage and activation of caspase 8 in response to TNF were not affected by MitoVit E, whereas the activation of caspase 3 was significantly increased. Furthermore, there was an increased cleavage of the proapoptotic Bcl-2 family member Bid and an increased release of cytochrome c from mitochondria, in cells treated with TNF in the presence of MitoVit E. We considered several mechanisms by which MitoVit E might accelerate TNF-induced apoptosis including mitochondrial integrity (ATP/ADP levels and permeability transition), alterations in calcium homoeostasis and transcription factor activation. Of these, only the transcription factor NF-κB (nuclear factor κB) was implicated. TNF caused maximal nuclear translocation of NF-κB within 15 min, compared with 1 h in cells pretreated with MitoVit E. Thus the accumulation of an antioxidant within the mitochondrial matrix enhances TNF-induced apoptosis by decreasing or delaying the expression of the protective antiapoptotic proteins. These results demonstrate that mitochondrial ROS production is a physiologically relevant component of the TNF signal-transduction pathway during apoptosis, and reveal a novel functional role for mitochondrial ROS as a temporal regulator of NF-κB activation and NF-κB-dependent antiapoptotic signalling.

scholarly journals Age-related loss of CpG methylation in the tumour necrosis factor promoter

Cytokine ◽  
2011 ◽  
Vol 56 (3) ◽  
pp. 792-797 ◽  
Author(s):  
Isobel R. Gowers ◽  
Kevin Walters ◽  
Endre Kiss-Toth ◽  
Robert C. Read ◽  
Gordon W. Duff ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Cpg Methylation ◽  
Age Related ◽  
Necrosis Factor

scholarly journals Mitochondrial transformations in the aging human placenta

2020 ◽  
Vol 319 (6) ◽  
pp. E981-E994
Author(s):  
Lucy A. Bartho ◽  
Joshua J. Fisher ◽  
James S. M. Cuffe ◽  
Anthony V. Perkins
Keyword(s):  
Human Placenta ◽  
Cell Biology ◽  
Later Life ◽  
Cellular Damage ◽  
Gestational Length ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Cellular Environment ◽  
Age Related ◽  
And Function

Mitochondria play a key role in homeostasis and are central to one of the leading hypotheses of aging, the free radical theory. Mitochondria function as a reticulated network, constantly adapting to the cellular environment through fusion (joining), biogenesis (formation of new mitochondria), and fission (separation). This adaptive response is particularly important in response to oxidative stress, cellular damage, and aging, when mitochondria are selectively removed through mitophagy, a mitochondrial equivalent of autophagy. During this complex process, mitochondria influence surrounding cell biology and organelles through the release of signaling molecules. Given that the human placenta is a unique organ having a transient and somewhat defined life span of ∼280 days, any adaption or dysfunction associated with mitochondrial physiology as a result of aging will have a dramatic impact on the health and function of both the placenta and the fetus. Additionally, a defective placenta during gestation, resulting in reduced fetal growth, has been shown to influence the development of chronic disease in later life. In this review we focus on the mitochondrial adaptions and transformations that accompany gestational length and share similarities with age-related diseases. In addition, we discuss the role of such changes in regulating placental function throughout gestation, the etiology of gestational complications, and the development of chronic diseases later in life.

scholarly journals Association of a RING finger protein with the cytoplasmic domain of the human type-2 tumour necrosis factor receptor

1995 ◽  
Vol 309 (3) ◽  
pp. 825-829 ◽  
Author(s):  
H Y Song ◽  
D B Donner
Keyword(s):  
Tumour Necrosis Factor ◽  
Hybrid System ◽  
Tumour Necrosis ◽  
Ring Finger ◽  
Tnf Receptor ◽  
Intracellular Domain ◽  
Two Hybrid ◽  
Necrosis Factor

A human gene encoding a protein that specifically binds to the intracellular domain of the 75 kDa type-2 tumour necrosis factor (TNF) receptor (TNFR-2IC) has been identified using the yeast-based two-hybrid system. The N-terminal half of the TNF receptor-associated protein (TRAP) contains RING finger and zinc finger motifs often found in DNA-binding proteins including transcription factors. The 2.4 kb TRAP mRNA was barely detectable, if present at all, in lung, and variably expressed in heart, liver, placenta, brain, skeletal muscle, kidney and the pancreas; interestingly, the TRAP was more highly expressed in transformed cell lines than in normal tissues. This observation may be consistent with a role for this TRAP in promoting or regulating cellular proliferation. After in vitro transcription/translation and 35S labelling the TRAP was precipitated using a fusion protein consisting of glutathione S-transferase and the intracellular domain of TNFR-2 (TNFR-2IC), which showed that the two proteins directly interact in a mammalian cell-free system and also that identification of the TRAP was not an artifact of the two-hybrid system. By using truncated TNFR-2ICs for in vitro precipitation of 35S-TRAP, it was shown that the C-terminal half of the TNFR-2IC contains the domain necessary for interaction with TRAP. The TRAP identified in the present study shares considerable homology with, and may be the human homologue of, a mouse protein, TNF receptor-associated factor 2 (TRAF2), that binds mouse TNFR-2.

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