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

STING mediates microglial pyroptosis via interaction with NLRP3 in cerebral ischaemic stroke DOI Creative Commons
Wenyu Li, Nan Shen,

Lingqi Kong

et al.

Stroke and Vascular Neurology, Journal Year: 2023, Volume and Issue: 9(2), P. 153 - 164

Published: July 3, 2023

Background Ischaemia-evoked neuroinflammation is a critical pathogenic event following ischaemic stroke. Gasdermin D (GSDMD)-associated pyroptosis represents type of inflammation-associated programmed cell death, which can exacerbate neuroinflammatory responses and brain damage. Stimulator interferon genes (STING) was recently described as vital innate immune adaptor protein associated with neuroinflammation. Nevertheless, the regulatory effects STING on microglial post-stroke have not been well elaborated. Methods STING-knockout wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO). small interfering RNA (siRNA) transfected into BV2 cells before oxygen-glucose deprivation/reoxygenation (OGD/R). STING-overexpressing adeno-associated virus (AAV) NOD-like receptor family pyrin domain containing 3 (NLRP3) siRNA administered by stereotaxic injection. 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, TdT-mediated dUTP nick end labeling (TUNEL) Fluoro-Jade C (FJC) neurobehavioural tests, immunohistochemistry, cytokine antibody array assay, transmission electron microscopy, immunoblot, Enzyme-linked immunosorbent assay (ELISA) quantitative real-time polymerase chain reaction (qRT-PCR) carried out. Co-immunoprecipitation assays used investigate interplay between NLRP3. Results expression increased after MCAO mainly detected microglia. deletion alleviated infarction, neuronal damage impairment in MCAO. knockout suppressed activation secretion inflammatory chemokines, accompanied mitigation pyroptosis. Specific upregulation AAV-F4/80-STING aggravated injury Mechanistically, co-immunoprecipitation showed that bound NLRP3 Supplementation reversed AAV-F4/80-STING-induced deterioration Conclusions The current findings indicate modulates NLRP3-mediated may serve therapeutic target induced ischaemic/reperfusion (I/R) injury.

Language: Английский

Citations

29
Potential Therapeutic Value of the STING Inhibitors DOI Creative Commons
Shangran Zhang, Runan Zheng, Yanhong Pan

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(7), P. 3127 - 3127

Published: March 31, 2023

The stimulator of interferon genes (STING) is a critical protein in the activation immune system response to DNA. It can participate inflammatory process by modulating inflammation-preferred translation program through STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or inducing secretion type I interferons (IFNs) and variety proinflammatory factors recruitment TANK-binding 1 (TBK1) regulatory factor 3 (IRF3) regulation nuclear kappa-B (NF-κB) pathway. Based on structure, location, function, genotype, mechanism STING, this review summarizes potential value STING inhibitors prevention treatment infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, other autoimmune diseases.

Language: Английский

Citations

23
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
The bidirectional roles of the cGAS-STING pathway in pain processing: Cellular and molecular mechanisms DOI Open Access

Yingjie Hu,

Yuye Chen, Tongtong Liu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 163, P. 114869 - 114869

Published: May 12, 2023

Pain is a common clinical condition. However, the mechanisms underlying pain are not yet fully understood. It known that neuroimmune system plays critical role in pathogenesis of pain. Recent studies indicated cyclic-GMP-AMP synthase-stimulator interferon genes (cGAS-STING) pathway can activate innate immune by sensing both extrinsic and intrinsic double-stranded DNA cytoplasm, which involved processing. In this review, we summarise (1) roles cGAS-STING different models, (2) effect cells during regulation, (3) downstream molecular regulation. This review provides evidence has pro- anti-nociceptive effects models. functions neuron, microglia, macrophage, T cells. Its molecules include IFN-I, NF-κB, NLRP3, eIF2α. The bidirectional processing mediated regulating nociceptive neuronal sensitivity neuroinflammatory responses. their special brain regions, activation astrocytes, phases require further exploration.

Language: Английский

Citations

15
Immunotherapies in chronic pain through modulation of neuroimmune interactions DOI Creative Commons
Junli Zhao, Yul Huh,

Andrey V. Bortsov

et al.

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 248, P. 108476 - 108476

Published: June 10, 2023

Language: Английский

Citations

13
The impact of neuroinflammation on neuronal integrity DOI Open Access
Bora Tastan, Michael T. Heneka

Immunological Reviews, Journal Year: 2024, Volume and Issue: 327(1), P. 8 - 32

Published: Oct. 1, 2024

Neuroinflammation, characterized by a complex interplay among innate and adaptive immune responses within the central nervous system (CNS), is crucial in responding to infections, injuries, disease pathologies. However, dysregulation of neuroinflammatory response could significantly affect neurons terms function structure, leading profound health implications. Although tremendous progress has been made understanding relationship between processes alterations neuronal integrity, specific implications concerning both structure have not extensively covered, with exception perspectives on glial activation neurodegeneration. Thus, this review aims provide comprehensive overview multifaceted interactions key inflammatory players, exploring mechanisms through which inflammation influences functionality structural integrity CNS. Further, it will discuss how these lead impairment functions architecture highlight consequences caused dysregulated functions, such as cognitive dysfunction mood disorders. By integrating insights from recent research findings, enhance our landscape set stage for future interventions that transform current approaches preserve CNS-related conditions.

Language: Английский

Citations

5
ZC3H15 suppression ameliorates bone cancer pain through inhibiting neuronal oxidative stress and microglial inflammation DOI Creative Commons
Liquan Huang, Tristan D. Yan, Baosheng Wang

et al.

Neoplasia, Journal Year: 2025, Volume and Issue: 61, P. 101123 - 101123

Published: Feb. 4, 2025

Language: Английский

Citations

0
Synergistic Inhibition of Nav1.7 and NCX1: A Novel Strategy for Treating Cancer‐Induced Bone Pain by Modulating Pain Sensitization and Neuronal Inflammation DOI Creative Commons

Yan Feng,

Yan Fang, Dongtai Chen

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(4)

Published: April 1, 2025

ABSTRACT Aims Cancer‐induced bone pain (CIBP) is a chronic and refractory condition characterized by neuronal hyperexcitability, calcium dysregulation, neuroinflammation. Voltage‐gated sodium channels (VGSCs) sodium/calcium exchangers (NCXs) are crucial in regulating sensory neuron sodium–calcium homeostasis, influencing nociceptive signaling neuroinflammatory responses. This study focused on exploring how Nav1.7 from the VGSC family NCX1 NCX influence neuroinflammation CIBP. Methods CIBP was induced mice. expression colocalization DRG neurons were analyzed qPCR, western blotting, immunofluorescence. Calcium overload excitability assessed using imaging electrophysiological recordings. Neuroinflammation markers detected qPCR blotting. Results Among subtypes, notably upregulated colocalized of Combined inhibition these demonstrated synergistic analgesic effect markedly reduced hyperexcitability. Furthermore, combined substantially alleviated inhibiting p38 MAPK/NF‐κB pathway lowering proinflammatory cytokine levels. Conclusions The enhances effects reduces neuroinflammation, presenting potential therapeutic approach for other cancer‐associated disorders.

Language: Английский

Citations

0
Decoding STING’s roles in cancer: immunity, pain, dormancy, and autophagy DOI
Huan‐Xin Lin, Ya‐ling Tang,

Xinhua Liang

et al.

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 24, 2025

Language: Английский

Citations

0
Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review DOI Creative Commons
Jinghan Yang, Hui Ding, Bo Shuai

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Jan. 4, 2023

Since the discovery of STING in 2008, numerous studies have investigated its functions immunity, inflammation, and cancer. activates downstream molecules including IFN-I, NLRP3, NF-κB. The STING–IFN-I pathway plays a vital role nociception. After receiving upstream signal, is activated induces expression after paracrine autocrine signaling, IFN-I binds to IFN receptors. Subsequently, activity ion channels inhibited by TYK2, which an acute antinociceptive effect. JAK PIK3 MAPK–MNK–eIF4E pathways, sensitize nociceptors peripheral nervous system. In mid-late stage, STAT, increases pro-inflammatory anti-inflammatory cytokines, inhibits ER-phagy, promotes microglial M1-polarization central system, leading sensitization. Thus, may exert complex effects on nociception at various stages, these require further comprehensive elucidation. Therefore, this review, we systematically summarized mechanisms discussed function

Language: Английский

Citations

10