A complex secretory program orchestrated by the inflammasome controls paracrine senescence

By J. Acosta, Ana Banito, T. Wuestefeld, A. Georgilis, Peggy Janich, J. Morton, D. Athineos, T. Kang, F. Lasitschka, M. Andrulis and 15 more. Nature Cell Biology, 2013

2,043 citations recorded by the source corpus.

Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15INK4b and p21CIP1. Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.

Subfields: Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/59786bed7ce43f9317328cd82838f14d911e5dd4

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In Immunology

1. J. Campisi
2. Jesús Gil
3. M. Demaria
4. Claudio Franceschi
5. Manuel Serrano
6. V. Krizhanovsky
7. P. Jat
8. R. Kumari

In Physiology

1. Jesús Gil
2. J. Campisi
3. M. Demaria
4. Manuel Serrano
5. Nicolás Herranz
6. Domhnall McHugh
7. P. Jat
8. R. Kumari

Citations in the corpus

• Senescence is a developmental mechanism that contributes to embryonic growth and patterning. (2013, background): “However, our data also suggest that the AERmay be subject to autocrine or local-paracrine influence on the senescent state within the AER, involving CEBP/b, transforming growth factor b (TGF-b), and p15 pathways (Acosta et al., 2013; Gomis et al., 2006; Hannon and Beach, 1994).”
• mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype (2015, positive): “1b and Supplementary Table 1), as previously described 6,10,11 .”
• Senescence and apoptosis: dueling or complementary cell fates? (2014, neutral): “For instance, it has been shown that senescence and SASP production can trigger senescence in neighboring cells via paracrine signaling, a phenomenon that has been referred to as bystander senescence [138].”
• Mechanisms and functions of cellular senescence. (2018, positive): “Indeed, IL-1 α signaling is sufficient to partially recapitulate the inflammatory SASP (68).”
• A proteomic atlas of senescence-associated secretomes for aging biomarker development (2019, background): “The SASP Atlas will be continuously updated with SASP profiles from new cell types and senescence, including paracrine (or bystander) senescence [49,50] as well as temporal dynamics of the SASP—all generated by our laboratories.”
• Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021, background): “Blocking PARP-1, ATM, or NF-κB in melanoma cells prevents the secretion of chemokine CCL2 thereby restricting the deleterious pro-invasive properties of the inflammatory SASP mediated by PNAS (Ohanna et al., 2011).”
• Measuring biological aging in humans: A quest (2019, result): “…to impairment in others, a notion that is strengthened by emerging evidence in recent literature, although most is derived from animal studies (Acosta et al., 2013; Chang et al., 2015; Childs, Li, & van Deursen, 2018; García-Prat et al., 2016; GonzalesEbsen, Gregersen, & Olsen, 2017; Hall et…”