Mechanisms and Regulation of Cellular Senescence DOI Open Access

Lauréline Roger,

Fanny Tomas,

Véronique Gire

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 13173 - 13173

Published: Dec. 6, 2021

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete range pro-inflammatory proteolytic factors as part the senescence-associated secretory phenotype. There are different types senescent cells, can be induced response to many DNA damage signals. Senescent accumulate tissues organs where they have distinct physiological pathological functions. Despite this diversity, all must able survive nondividing while protecting themselves from positive feedback loops linked constant activation response. This capacity requires changes core cellular programs. Understanding how cell undergo extensive their transcriptional programs, metabolism, heterochromatin patterns, structures induce common is crucial preventing cancer development/progression improving health during aging. In review, we discuss continuously evolve after initial highlight unifying features that define state.

Language: Английский

Mitochondria as multifaceted regulators of cell death DOI
Florian J. Bock, Stephen W. G. Tait

Nature Reviews Molecular Cell Biology, Journal Year: 2019, Volume and Issue: 21(2), P. 85 - 100

Published: Oct. 21, 2019

Language: Английский

Citations

1894
Inflammation and tumor progression: signaling pathways and targeted intervention DOI Creative Commons

Huakan Zhao,

Lei Wu,

Guifang Yan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 12, 2021

Abstract Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates progression treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation dendritic cells (DCs) antigen presentation, leading anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers activators transcription (JAK-STAT), toll-like receptor (TLR) cGAS/STING, mitogen-activated protein kinase (MAPK); factors, including cytokines (e.g., interleukin (IL), interferon (IFN), necrosis (TNF)-α), chemokines C-C motif chemokine ligands (CCLs) C-X-C (CXCLs)), growth factors vascular endothelial (VEGF), transforming (TGF)-β), inflammasome; well metabolites prostaglandins, leukotrienes, thromboxane, specialized proresolving mediators (SPM), have been identified pivotal regulators initiation resolution inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, SPM developed specifically modulate in cancer therapy, with some these already undergoing clinical trials. Herein, we discuss crosstalk between processes. We also highlight potential targets for harnessing cancer.

Language: Английский

Citations

1611
The cGAS–STING pathway as a therapeutic target in inflammatory diseases DOI Open Access
Alexiane Decout, Jason D. Katz,

Shankar Venkatraman

et al.

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(9), P. 548 - 569

Published: April 8, 2021

Language: Английский

Citations

1369
DNA sensing by the cGAS–STING pathway in health and disease DOI
Mona Motwani,

Scott Pesiridis,

Katherine A. Fitzgerald

et al.

Nature Reviews Genetics, Journal Year: 2019, Volume and Issue: 20(11), P. 657 - 674

Published: July 29, 2019

Language: Английский

Citations

1106
Caspases in Cell Death, Inflammation, and Disease DOI Creative Commons
Nina Van Opdenbosch, Mohamed Lamkanfi

Immunity, Journal Year: 2019, Volume and Issue: 50(6), P. 1352 - 1364

Published: June 1, 2019

Language: Английский

Citations

971
The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer DOI Open Access
John Kwon, Samuel F. Bakhoum

Cancer Discovery, Journal Year: 2019, Volume and Issue: 10(1), P. 26 - 39

Published: Dec. 18, 2019

The recognition of DNA as an immune-stimulatory molecule is evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. cGAS-STING pathway was discovered important DNA-sensing machinery in immunity and viral defense. Recent advances have now expanded the roles cancer. Highly aggressive, unstable tumors evolved co-opt this program drive tumorigenic behaviors. In review, we discuss link between antitumor well cancer progression, genomic instability, tumor microenvironment, pharmacologic strategies for therapy. SIGNIFICANCE: defense infections. Given its role activating surveillance, it has been assumed that primarily functions a suppressor. Yet, mounting evidence suggests depending on context, signaling can also metastasis-promoting functions, chronic activation paradoxically induce immune-suppressive microenvironment.

Language: Английский

Citations

866
Consensus guidelines for the definition, detection and interpretation of immunogenic cell death DOI Creative Commons
Lorenzo Galluzzi, Ilio Vitale, Sarah H. Warren

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2020, Volume and Issue: 8(1), P. e000337 - e000337

Published: March 1, 2020

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular microenvironmental features determine the propensity of RCD drive immunity. Here, we provide updated operational definition immunogenic (ICD), discuss key factors that dictate ability dying cells response, summarize experimental assays are currently available for assessment ICD in vitro vivo, formulate guidelines their interpretation.

Language: Английский

Citations

849
Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway DOI Creative Commons
Xuewu Zhang, Xiao‐chen Bai, Zhijian J. Chen

et al.

Immunity, Journal Year: 2020, Volume and Issue: 53(1), P. 43 - 53

Published: July 1, 2020

Language: Английский

Citations

511
The cGAS–STING pathway drives type I IFN immunopathology in COVID-19 DOI Creative Commons
Jérémy Di Domizio, Muhammet F. Gülen, Fanny Saidoune

et al.

Nature, Journal Year: 2022, Volume and Issue: 603(7899), P. 145 - 151

Published: Jan. 19, 2022

Abstract COVID-19, which is caused by infection with SARS-CoV-2, characterized lung pathology and extrapulmonary complications 1,2 . Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3–5 ). Although rapid induction type IFNs limits virus propagation, a sustained increase levels late phase associated aberrant inflammation poor clinical outcome 5–17 Here we show that cyclic GMP-AMP synthase (cGAS)–stimulator interferon genes (STING) pathway, controls immunity to cytosolic DNA, critical driver IFN responses (ref. 18 Profiling skin manifestations, uncover STING-dependent signature primarily mediated macrophages adjacent areas endothelial cell damage. Moreover, cGAS–STING activity was detected samples from patients prominent tissue destruction, responses. A lung-on-chip model revealed that, addition macrophages, SARS-CoV-2 activates signalling cells through mitochondrial DNA release, leads death production. In mice, pharmacological inhibition STING reduces severe induced improves disease outcome. Collectively, our study establishes mechanistic basis pathological reveals principle for development host-directed therapeutics.

Language: Английский

Citations

416
cGAS–STING drives ageing-related inflammation and neurodegeneration DOI Creative Commons
Muhammet F. Gülen,

Natasha Samson,

Alexander Keller

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7973), P. 374 - 380

Published: Aug. 2, 2023

Low-grade inflammation is a hallmark of old age and central driver ageing-associated impairment disease1. Multiple factors can contribute to inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling their impact in natural ageing remain unclear. Here we show cGAS-STING pathway, which mediates immune sensing DNA3, critical chronic functional decline during ageing. Blockade STING suppresses phenotypes senescent human cells tissues, attenuates ageing-related multiple peripheral organs brain mice, leads an improvement tissue function. Focusing on brain, reveal activation triggers reactive microglial transcriptional states, neurodegeneration cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity microglia, defining mechanism by engaged brain. Single-nucleus RNA-sequencing analysis microglia hippocampi gain-of-function mouse model demonstrates engagement sufficient direct states leading bystander cell inflammation, neurotoxicity impaired memory capacity. Our findings establish pathway as blockade potential strategy halt neurodegenerative processes age.

Language: Английский

Citations

414