Neutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner

Lagnado, Anthony B.; Leslie, Jack; Ruchaud-Sparagano, Marie Hélène; Victorelli, Stella; Hirsova, Petra; Ogrodnik, Mikołaj; Collins, Amy; Vizioli, Maria Grazia; Habiballa, Leena; Saretzki, Gabriele; Evans, Shane A.; Salmonowicz, Hanna; Hruby, Adam; Geh, Daniel; Pavelko, Kevin D.; Dolan, David; Reeves, Helen L.; Grellscheid, Sushma Nagaraja; Wilson, Colin; Pandanaboyana, Sanjay; Doolittle, Madison L.; Zglinicki, Thomas von; Oakley, Fiona; Gallage, Suchira; Wilson, Caroline; Birch, Jodie; Carroll, Bernadette; Chapman, James; Heikenwälder, Mathias; Neretti, Nicola; Khosla, Sundeep; Masuda, Cláudio A.; Tchkonia, Tamar; Kirkland, James L.; Jurk, Diana; Mann, Derek A.; Passos, João F.

doi:10.15252/embj.2020106048

Cited by 128 publications

(114 citation statements)

References 62 publications

(80 reference statements)

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“…However, infection is capable to trigger accelerated TL attrition in telomerase-deficient mice [ 49 ], revealing the existence of telomerase-independent mechanisms linking inflammation to TL shortening. These mechanisms might include the production of ROS during inflammation; for example, via secretion by immune cells such as neutrophils [ 50 ]. Indeed, the rate of telomere shortening increases under oxidative stress, and the G-richness of telomeric DNA renders it highly susceptible to oxidization, leading to the accumulation of 8-oxo-guanine.…”

Section: Telomere Response To Stressmentioning

confidence: 99%

“…Some antioxidant proteins are associated with telomeres (PRDX1 and MTH1) [ 169 , 170 ]. Recently, it was shown that the ROS secreted by activated neutrophils leads to teloxidation of neighboring cells and senescence [ 50 ]. Besides, extra telomeric functions of the telomerase subunits TERT and TERC have been related to modulating mitochondrial metabolism.…”

Section: The Telomere Hormesis Hypothesismentioning

confidence: 99%

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The Power of Stress: The Telo-Hormesis Hypothesis

Burbano

Gilson

2021

Cells

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Adaptative response to stress is a strategy conserved across evolution to promote survival. In this context, the groundbreaking findings of Miroslav Radman on the adaptative value of changing mutation rates opened new avenues in our understanding of stress response. Inspired by this work, we explore here the putative beneficial effects of changing the ends of eukaryotic chromosomes, the telomeres, in response to stress. We first summarize basic principles in telomere biology and then describe how various types of stress can alter telomere structure and functions. Finally, we discuss the hypothesis of stress-induced telomere signaling with hormetic effects.

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Section: Telomere Response To Stressmentioning

confidence: 99%

Section: The Telomere Hormesis Hypothesismentioning

confidence: 99%

The Power of Stress: The Telo-Hormesis Hypothesis

Burbano

Gilson

2021

Cells

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“…We observed that many of the genomic regions which had the highest increases in ⍰H2AX and H4K16ac in steatosis, also had relatively high levels (compared to the rest of the genome) in cells grown in control media. This suggests that these regions, such as the telomere-proximal cluster which contains TERT , may be predisposed for sensitivity 33 . There is an abundance of recent literature on the role of epigenetic modifications altering the expression of TERT in cancer via transcriptional and post-transcriptional mechanisms 34 , but the potential for the epigenetic states promoting mutagenesis has been hypothetical 35 .…”

Section: Discussionmentioning

confidence: 99%

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Assante

Chandrasekaran

et al. 2021

Preprint

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The rate of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically-driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker γH2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.

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“…Recruited neutrophils promote the activation of fibroblasts and contribute to the turnover of the extracellular matrix in both normal and pathologic wound healing [ 18 ]. Furthermore, IL-8 is consistently observed in SASP [ 19 ] and paracrine signaling by neutrophils has been demonstrated to cause cellular senescence [ 20 , 21 ]. However, the specific role of cellular senescence in MWCNT induced fibrotic responses is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Multi-Walled Carbon Nanotubes (MWCNTs) Cause Cellular Senescence in TGF-β Stimulated Lung Epithelial Cells

Lucas

Wang

Muthumalage

et al. 2021

Toxics

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Multi-walled carbon nanotubes are engineered nanomaterials (ENMs) that have a fiber-like structure which may be a concern for the development of cellular senescence. Premature senescence, a state of irreversible cell cycle arrest, is implicated in the pathogenesis of chronic lung diseases such as pulmonary fibrosis (PF). However, the crosstalk between downstream pathways mediating fibrotic and senescent responses of MWCNTs is not well-defined. Here, we exposed human bronchial epithelial cells (BEAS-2B) to MWCNTs for up to 72 h and demonstrate that MWCNTs increase reactive oxygen species (ROS) production accompanied by inhibition of cell proliferation. In addition, MWCNT exposure resulted in the increase of p21 protein abundance and senescence associated β-galactosidase (SA β-gal) activity. We also determined that co-exposure with the cytokine, transforming growth factor-β (TGF-β) exacerbated cellular senescence indicated by increased protein levels of p21, p16, and γH2A.X. Furthermore, the production of fibronectin and plasminogen activator inhibitor (PAI-1) was significantly elevated with the co-exposure compared to MWCNT or TGF-β alone. Together, our study suggests that the cellular senescence potential of MWCNTs may be enhanced by pro-fibrotic mediators, such as TGF-β in the surrounding microenvironment.

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Neutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner

Cited by 128 publications

References 62 publications

The Power of Stress: The Telo-Hormesis Hypothesis

The Power of Stress: The Telo-Hormesis Hypothesis

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Multi-Walled Carbon Nanotubes (MWCNTs) Cause Cellular Senescence in TGF-β Stimulated Lung Epithelial Cells

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