Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction DOI Creative Commons
Úrzula Franco‐Enzástiga, Keerthana Natarajan, Eric T. David

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 5, 2023

Type I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation STING is a key component type IFN induction. Manipulation an active area investigation cancer and other therapeutic areas. Vinorelbine chemotherapeutic that activates has been shown cause neuropathy oncology clinical trials patients. There are conflicting reports on whether promotes or inhibits We hypothesized vinorelbine would neuropathic pain-like state mice pathways DRG associated with (10 mg/kg, i.v.) induced tactile allodynia grimacing WT male female increased p-IRF3 protein peripheral nerves. In support our hypothesis, vinorelbine-mediated was absent Sting

Language: Английский

cGAS–STING, an important signaling pathway in diseases and their therapy DOI Creative Commons
Qijie Li,

Ping Wu,

Qiujing Du

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(4)

Published: March 23, 2024

Abstract Since cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism cGAS–STING past decade. Meanwhile, triggering transduction mechanisms have continuously illuminated. plays a key role human diseases, particularly DNA‐triggered inflammatory making it potentially effective therapeutic target for inflammation‐related diseases. Here, we aim summarize ancient origin defense mechanism, as well triggers, transduction, cGAS–STING. We will also focus on important roles signal under pathological conditions, such infections, cancers, autoimmune neurological visceral inflammations, review drug development targeting pathway. The main directions potential obstacles research diseases cancers be discussed. These advancements expand our understanding cGAS–STING, provide theoretical basis further exploration open up new strategies promising intervention multiple

Language: Английский

Citations

23
Mitophagy and cGAS–STING crosstalk in neuroinflammation DOI Creative Commons
Xiaogang Zhou, Jing Wang, Lu Yu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3327 - 3361

Published: May 13, 2024

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial innate immunity. This pathway responds DNA and associated with cellular stress. Our review explores molecular details regulatory mechanisms of mitophagy pathway. We critically evaluated literature demonstrating how dysfunctional leads neuroinflammatory conditions, primarily through accumulation mitochondria, activating activation prompts production proinflammatory cytokines, exacerbating neuroinflammation. emphasizes interaction between Effective might suppress offering protection against Conversely, impaired may activate potentially leading chronic Additionally, we explored this influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there need additional targeted research unravel complexities mitophagy–cGAS–STING interactions their role neurodegeneration. highlights potential therapies targeting these pathways, which could lead new treatments conditions. synthesis enhances our understanding foundations neuroinflammation opens therapeutic avenues disease research.

Language: Английский

Citations

16
Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice DOI Creative Commons
Arthur Silveira Prudente, Sang Hoon Lee,

Jueun Roh

et al.

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 117, P. 51 - 65

Published: Jan. 6, 2024

Microglia, resident immune cells in the central nervous system, play a role neuroinflammation and development of neuropathic pain. We found that stimulator interferon genes (STING) is predominantly expressed spinal microglia upregulated after peripheral nerve injury. However, mechanical allodynia, as marker pain following injury, did not require microglial STING expression. In contrast, activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated male mice, but female mice. mice leads to increase proinflammatory cytokines may counteract analgesic effect ADU-S100. Microglial expression type I interferon-ß (IFN-ß) signaling were required for effects Mechanistically, downstream TANK-binding kinase 1 (TBK1) production IFN-ß, partly account observed. These findings suggest could be potential therapeutic intervention pain, particularly males.

Language: Английский

Citations

9
Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction DOI Creative Commons
Úrzula Franco‐Enzástiga, Keerthana Natarajan, Eric T. David

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(2), P. 108808 - 108808

Published: Jan. 8, 2024

Type I interferons (IFNs) increase the excitability of dorsal root ganglia (DRGs) neurons via MNK-eIF4E signaling to promote pain sensitization in mice. Activation stimulator interferon response cGAMP interactor 1 (STING) is pivotal for type IFN induction. We hypothesized that vinorelbine, a chemotherapeutic and activator STING, would cause neuropathic pain-like state mice STING DRG associated with production. Vinorelbine caused tactile allodynia grimacing wild-type (WT) increased p-IRF3, IFNs, p-eIF4E peripheral nerves. Supporting our hypothesis, vinorelbine failed induce IRF3-IFNs-MNK-eIF4E StingGt/Gt and, subsequently, pain. The vinorelbine-elicited was not observed Mknk1−/− (MNK1 knockout) nerves consistent attenuated pro-nociceptive effect these Our findings show activation periphery causes through nociceptors.

Language: Английский

Citations

6
CMPK2 facilitates pain sensitization by promoting the lactylation and deactivation of cGAS-STING pathway in neuropathic pain DOI Creative Commons
Mei Yang, Erliang Kong,

Honghao Song

et al.

Brain Behavior and Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Neuronal STING–GAT1 signaling maintains paclitaxel-induced neuropathic pain in the spinal cord DOI

Thuỳ Linh Phạm,

Ramesh Sharma, Chiranjivi Neupane

et al.

Pain, Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

Stimulator of interferon genes (STING), a pivotal immune regulator, has emerged as contributor to nociception, yet its role in chronic pains remains still unknown. Here, we demonstrate that STING plays dual normal and neuropathic pain mature male rodents. maintains type I (IFN-I) level restraining sensitivity sham control, while activated STING/interferon regulatory factor 3 (IRF3) signaling increases the expression gamma-aminobutyric acid (GABA) transporter 1 (GAT1) spinal cord (SC), thus, generating paclitaxel (PTX)-induced peripheral neuropathy. Genetic interference (STING-/- mice) attenuated PTX-induced mechanical hypersensitivity with GAT1 increase, preventing increase tonic GABAA inhibition dorsal horn neurons. regulates GAT through TANK-binding kinase (TBK1)-IRF3 pathway, IRF3 crucial transcription factor. Silencing neuronal STING, opposed astrocytic counterpart, effectively restrained SC. Pharmacological (H-151) efficiently diminished TBK1/IRF3/GAT1 pathway alleviate hypersensitivity. Our findings show STING-IRF3 serves role: suppressing physiological nociception IFN-I acting transcriptional regulator GAT1, contributing chemotherapy-induced pain.

Language: Английский

Citations

0
The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases DOI Creative Commons
Yuxin Zhang, Meijuan Zou, Hao Wu

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 202, P. 106710 - 106710

Published: Oct. 28, 2024

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by damage to specific cell populations in the nervous system, ultimately leading disability or death. Effective treatments for these still lacking, due limited understanding their pathogeneses, which involve multiple cellular and molecular pathways. The triggering an immune response is feature neurodegenerative disorders. A critical challenge intricate interplay between neuroinflammation, neurodegeneration, responses, not yet fully characterized. In recent years, cyclic GMP-AMP synthase (cGAS)-stimulator interferon gene (STING) pathway, crucial intracellular DNA sensing, has gradually gained attention. However, roles this pathway within types such as cells, glial neuronal its contribution ND pathogenesis, remain elucidated. review, we systematically explore how cGAS-STING signaling links various with related effector pathways under context NDs multifaceted therapeutic directions. We emphasize discovery condition-dependent heterogeneity integral diverse responses potential targets. Additionally, review pathogenic role activation Parkinson's disease, ataxia-telangiectasia, amyotrophic lateral sclerosis. focus on complex bidirectional Alzheimer's Huntington's sclerosis, revealing double-edged nature disease progression. objective elucidate pivotal pathogenesis catalyze new insights facilitating development novel strategies.

Language: Английский

Citations

3
Inhibition of spinal BRD4 alleviates pyroptosis and M1 microglia polarization via STING-IRF3 pathway in morphine-tolerant rats DOI Creative Commons
Xiaoqian Jia, Jie Ju, Zheng Li

et al.

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 969, P. 176428 - 176428

Published: March 1, 2024

Morphine tolerance has been a challenging medical issue. Neuroinflammation is considered as critical mechanism for the development of morphine tolerance. Bromodomain-containing protein 4 (BRD4), key regulator in cell damage and inflammation, participates chronic pain. However, whether BRD4 involved underlying mechanisms remain unknown. The morphine-tolerant rat model was established by intrathecal administration twice daily 7 days. Behavior test assessed tail-flick latency test. roles BRD4, pyroptosis, microglia polarization related signaling pathways were elucidated Western blot, real-time quantitative polymerase chain reaction, immunofluorescence. Repeated upregulated level, induced promoted M1-polarization spinal cord, accompanied release proinflammatory cytokines, such TNF-α IL-1β. JQ-1, antagonist, alleviated tolerance, diminished pyroptosis switch from M1 to M2 phenotype. Mechanistically, stimulator interferon gene (STING)- regulatory factor 3 (IRF3) pathway activated protective effect JQ-1 against at least partially mediated inhibition STING-IRF3 pathway. This study demonstrated first time that contributes via during which extend understanding neuroinflammation provide an alternative strategy precaution this condition.

Language: Английский

Citations

2
STING recognition of viral dsDNA by nociceptors mediates pain in mice DOI Creative Commons
Sang Hoon Lee,

Fabio Bonifacio,

Arthur Silveira Prudente

et al.

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 121, P. 29 - 42

Published: July 22, 2024

Pain is often one of the initial indicators a viral infection, yet our understanding how viruses induce pain limited. Immune cells typically recognize nucleic acids, which activate receptors and signaling, leading to immunity. Interestingly, these signals are also present in nociceptors associated with pain. Here, we investigate response acids during infections, specifically focusing on role signal, Stimulator Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers responses through STING expression nociceptors. In addition, agonists alone can elicit responses. Notably, involve direct activation TRPV1. We provided proof-of-concept showing TRPV1 significantly contribute mechanical hypersensitivity induced by HSV-1 infection. These findings suggest could be potential therapeutic target for relieving infections.

Language: Английский

Citations

2
Activation of mitochondrial DNA-mediated cGAS-STING pathway contributes to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord DOI
Yuye Chen,

Yingjie Hu,

Xiao He

et al.

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 127, P. 111348 - 111348

Published: Dec. 12, 2023

Language: Английский

Citations

5