STING orchestrates the neuronal inflammatory stress response in multiple sclerosis

Cell, Journal Year: 2024, Volume and Issue: 187(15), P. 4043 - 4060.e30

Published: June 14, 2024

Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce stimulator interferon genes (STING). However, activation STING requires detachment from stromal interaction molecule 1 (STIM1), process triggered by glutamate excitotoxicity. This initiates non-canonical signaling, which leads to autophagic degradation glutathione peroxidase 4 (GPX4), essential for redox homeostasis thereby inducing ferroptosis. Both genetic pharmacological interventions target protect against inflammation-induced neurodegeneration. Our findings position as central regulator detrimental integrating inflammation with signaling cause cell death, present it tractable treating MS.

Language: Английский

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The senescence journey in cancer immunoediting

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 1, 2024

Abstract Cancer progression is continuously controlled by the immune system which can identify and destroy nascent tumor cells or inhibit metastatic spreading. However, its deregulated activity in microenvironment also promote favoring outgrowth of cancers capable escaping control, a process termed cancer immunoediting. This process, has been classified into three phases, i.e. “elimination”, “equilibrium” “escape”, influenced several cancer- microenvironment-dependent factors. Senescence cellular program primed response to different pathophysiological stimuli, based on long-lasting cell cycle arrest secretion numerous bioactive inflammatory molecules. Because this, senescence potent immunomodulatory factor promptly recruiting actively promoting tissue remodeling. In context cancer, these functions lead both immunosurveillance immunosuppression. this review, authors will discuss role immunoediting, highlighting context- timing-dependent effects describing how senescent recruitment for elimination sustain inflammation escape. A potential contribution dormancy, as mechanism therapy resistance relapse, be discussed with final objective unravel immunotherapeutic implications modulation cancer.

Language: Английский

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The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(6), P. 733 - 750

Published: April 11, 2024

Abstract The accumulation of senescent cells within tissues is a hallmark the aging process. Senescent are also commonly present in many age-related diseases and cancer microenvironment. escape abnormal from immune surveillance indicates that there some defect function cytotoxic cells, e.g., CD8 + T natural killer (NK) cells. Recent studies have revealed expression programmed death-ligand 1 (PD-L1) protein abundantly increased An increase amount PD-L1 protects clearance by PD-1 checkpoint receptor In fact, activation suppresses properties NK promoting state immunosenescence. inhibitory PD-1/PD-L1 pathway acts cooperation with immunosuppressive cells; for example, can enhance differentiation regulatory (Treg), myeloid-derived suppressor (MDSC), M2 macrophages, whereas cytokines secreted stimulate protein. Interestingly, signaling pathways known to promote cellular senescence process crucial stimulators protein, epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, AhR signaling. It seems axis has role thus it promotes tissues. Thus, blockade might be potential anti-aging senolytic therapy. Key messages accumulate during diseases. able Expression markedly increases Age-related stimulates Inhibitory

Language: Английский

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Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity

Science Advances, Journal Year: 2024, Volume and Issue: 10(3)

Published: Jan. 17, 2024

Bone is one of the most common sites tumor metastases. During last step bone metastasis, cancer cells colonize and disrupt matrix, which maintained mainly by osteocytes, abundant in microenvironment. However, role osteocytes metastasis still unclear. Here, we demonstrated that transfer mitochondria to metastatic trigger cGAS/STING-mediated antitumor response. Blocking specifically knocking out mitochondrial Rho GTPase 1 ( Rhot1 ) or mitofusin 2 Mfn2 impaired immunogenicity consequently resulted progression toward matrix. These findings reveal protective against transferring potentially offer a valuable therapeutic strategy for preventing metastasis.

Language: Английский

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Oxidized mitochondrial DNA activates the cGAS-STING pathway in the neuronal intrinsic immune system after brain ischemia-reperfusion injury

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(4), P. e00368 - e00368

Published: April 30, 2024

In the context of stroke and revascularization therapy, brain ischemia-reperfusion injury is a significant challenge that leads to oxidative stress inflammation. Central cell's intrinsic immunity cGAS-STING pathway, which typically activated by unusual DNA structures. The involvement oxidized mitochondrial (ox-mtDNA)-an byproduct-in this type neurological damage has not been fully explored. This study among first examine effect ox-mtDNA on innate neurons following injury. Using rat model transient middle cerebral artery occlusion cellular oxygen-glucose deprivation/reoxygenation, we have discovered activates pathway in neurons. Importantly, pharmacologically limiting release into cytoplasm reduces inflammation improves functions. Our findings suggest targeting may be valuable strategy attenuate therapy for acute ischemic stroke.

Language: Английский

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Regulation of cGAS–STING signalling and its diversity of cellular outcomes

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: Английский

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The cGAS–STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(2)

Published: Jan. 7, 2025

Ataxia–telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of homeostatic protein kinase ATM. The complex phenotype A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts patients exhibit senescence, highlighting association between cellular We found that derived ATM-deficient mice provide versatile experimental system to explore mechanisms driving senescence primary lacking Atm −/− failed proliferate under ambient oxygen conditions (21%). Although they initially proliferated physiological levels (3%), rapidly entered senescence. In contrast, wild-type (WT) did not senesce 3% eventually underwent immortalization neoplastic transformation. However, rapid could be induced in WT cells either by gene ablation or persistent chemical inhibition ATM activity, with being reversible upon inhibitor removal. Moreover, concomitant p53 led evasion, vigorous growth, rampant subsequent Our findings reveal driven collaborative action cGAS–STING, p38 MAPK, pathways response DNA damage, ultimately leading induction interferon-α1 downstream interferon-stimulated genes. propose accelerated may exacerbate specific symptoms, particularly contributing progressive, life-threatening disease often observed during adulthood.

Language: Английский

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Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 17, 2025

Drug resistance is a common challenge in clinical tumor treatment. A reduction drug sensitivity of cells often accompanied by an increase autophagy levels, leading to autophagy-related resistance. The effectiveness combining chemotherapy drugs with inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected various types autophagy. Therefore, ferroptosis have crosstalk via autophagy, potentially switch cell death under certain conditions. As two forms inflammatory programmed death, different effects on inflammation, cGAS-STING signaling pathway also involved. it plays important role progression some chronic diseases. This review discusses relationship between pyroptosis, attempts uncover reasons behind evasion nature

Language: Английский

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Clinical Chemotherapeutic Agent Coordinated Copper‐Based Nanoadjuvants for Efficiently Sensitizing Cancer Chemo‐Immunotherapy by Cuproptosis‐Mediated Mitochondrial Metabolic Reprogramming

Advanced Functional Materials, Journal Year: 2023, Volume and Issue: 33(51)

Published: Aug. 17, 2023

Abstract Chemo‐immunotherapy has shown great success in boosting systemic anti‐tumor effects the clinic. However, cancer cells can escape maximum impact of chemotherapy through intracellular symbiotic bacteria and abnormally activated macropinocytosis, while immune evasion is largely facilitated by programmed cell death 1 ligand (PD‐L1) protein tumor‐secreted exosomes. To efficiently sensitize chemo‐immunotherapy, clinical mitoxantrone (MTO) therefore rationally coordinated with Cu 2+ to develop nanoscale metal‐organic frameworks (MTO‐Cu), then loaded macropinocytosis exosome secretion inhibitor amiloride (AMI) modified targeted chondroitin sulfate (CS) form CS/MTO‐Cu@AMI nanoadjuvant. Notably, effectively triggers cuproptosis‐induced mitochondrial dysfunction, which activates AMPK pathway‐mediated PD‐L1 degradation, deprives energy supply for release, amplifies oxidative stress deactivating bacteria, thus sensitizing chemo‐immunotherapy. Meanwhile, AMI suppresses act synergistically ‐caused chemo‐immunotherapy potentiation. Moreover, damaged dsDNA during treatment cGAS‐STING pathway, further evoking immunity. Additionally, attached CS endows specific tumor targeting hyaluronidase‐responsive charge reversal property, MTO‐Cu this nanoadjuvant pH/GSH dual‐responsive release behavior. Therefore, sensitizes antitumor immunity vitro vivo, providing an innovative solution potentiate

Language: Английский

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cGAS-STING signaling in the tumor microenvironment

Cancer Letters, Journal Year: 2023, Volume and Issue: 577, P. 216409 - 216409

Published: Sept. 23, 2023

Language: Английский

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