A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Acosta, Juan Carlos; Banito, Ana; Wüestefeld, Torsten; Georgilis, Athena; Janich, Peggy; Morton, Jennifer P.; Athineos, Dimitris; Kang, Tae‐Won; Lasitschka, Felix; Andrulis, Mindaugas; Pascual, Gloria; Morris, Kelly J.; Khan, Sadaf; Jin, Hong; Dharmalingam, Gopuraja; Snijders, Ambrosius P.; Carroll, Thomas; Capper, David; Pritchard, Catrin; Inman, Gareth J.; Longerich, Thomas; Sansom, Owen J.; Benitah, Salvador Aznar; Zender, Lars; Gil, Jesús

doi:10.1038/ncb2784

Cited by 1,737 publications

(1,783 citation statements)

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“…While the formation of myofibroblasts during wound healing in a mouse model system was reported to be stimulated by SASP factors secreted from senescent fibroblasts and endothelial cells generated at the site of injury (Demaria et al, 2014), other studies demonstrated that, paradoxically, the SASP causes bystander senescence in somatic human fibroblasts (Acosta et al, 2013; Hubackova et al, 2012; Nelson et al, 2012). Recent studies, however, have raised the possibility that the SASP can promote development of myofibroblasts, as fibroblast incubated with conditioned medium from senescent cells develop into contractile α‐SMA‐expressing cells (Schafer et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, conditioned medium from senescent fibroblasts, as well as a number of molecules contained within this secretome including TGF‐β1 and IL1, can cause cellular senescence in neighboring fibroblasts through paracrine mechanisms (Acosta et al, 2013; Hubackova et al, 2012; Nelson et al, 2012). This bystander senescence is a consequence of cytokine‐mediated production of reactive oxygen species (ROS), which ultimately cause the formation of DSBs and activation of a persistent DDR in neighboring cells (Hubackova et al, 2012; Nelson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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Cells that had undergone telomere dysfunction‐induced senescence secrete numerous cytokines and other molecules, collectively called the senescence‐associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF‐β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS‐dependent manner. Surprisingly, instead of activating cellular senescence, TGF‐β1‐induced telomere dysfunction caused fibroblasts to transdifferentiate into α‐SMA‐expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF‐β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF‐β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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“…Senescence is a phenotypic switch committing a cell to stable growth arrest through activation of the cyclin dependent kinase inhibitor 2a (also known as p16 INK4A )/ retinoblastoma tumour suppressor pathway 155 and secretion of a range of factors, collectively denoted the senescence associated secretory phenotype (SASP), which includes pro inflammatory cytokines, matrix pro teases, and members of the transforming growth factor β family 156 . The SASP is, therefore, implicated in autocrine, paracrine, and even distant signalling (reviewed previ ously 157 ), which contributes to spreading of senescence to neighbouring cardiomyocytes and other cardiac cells.…”

Section: Cellular Senescencementioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…CD4 + CD25 Hi FoxP3 + Treg cells exercise their immunosuppressive functions by also inducing senescence on inflammatory T cells, which in turn will be converted into new immunomodulatory cells. Although senescence can be eventually propagated from cell to cell by a bystander effect (Acosta et al ., 2013), the mechanism underlying the suppressive effect of senescent T cells remains largely unknown.…”

Section: Summary and Perspectives: An Integrated View Of Cellular Senmentioning

confidence: 99%

Cellular senescence impact on immune cell fate and function

et al. 2016

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SummaryCellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T‐lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T‐helper lymphocyte‐dependent tissue homeostatic functions and T‐regulatory cell‐dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide‐reaching role as a homeostatic orchestrator.

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A complex secretory program orchestrated by the inflammasome controls paracrine senescence

Cited by 1,737 publications

References 53 publications

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Proteostasis in cardiac health and disease

Cellular senescence impact on immune cell fate and function

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