Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain

Wu, Wenyao; Zhang, Xianwei; Wang, Shuo; Li, Tian; Hao, Quanshui; Li, Shiyong; Yao, Wenlong

doi:10.1016/j.neuropharm.2022.109206

Cited by 35 publications

(27 citation statements)

References 64 publications

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“…After activation of JAKs, the mitogen-activated protein kinase (MAPK)–interacting kinase (MNK)–eukaryotic translation initiation factor 4E (eIF4E) pathway and PIK3 are activated, causing nociceptor sensitization in the PNS at a later stage ( Tan et al, 2021 ). In the mid-late stage, IFN-I activates STAT to induce the expression of pro-inflammatory and anti-inflammatory cytokines, inhibits ER-phagy, and promotes microglial M1-polarization, which generates delayed nociceptive effects in the CNS ( Figure 2 ; Ivashkiv and Donlin, 2014 ; Michalska et al, 2018 ; Tan et al, 2021 ; Wu et al, 2022 ).…”

Section: Mechanism Of Sting–ifn-i Pathway With Respect To Painmentioning

confidence: 99%

“…In the spared nerve injury (SNI) model, inhibiting the cGAS–STING pathway can restrain microglial M1-polarization and attenuate neuropathic pain ( Wu et al, 2022 ). M1-polarization microglia express CD16 and induce TNF-α and IL-1β synthesis, which may cause central sensitization ( Mesquida-Veny et al, 2021 ).…”

Section: Effects Of Sting–ifn-i Pathway On Nociceptionmentioning

confidence: 99%

“…First, the sex of the animals may have caused this discrepancy. This pathway more likely has a negative effect on male rats ( Wu et al, 2022 ). Second, animal experiments were used to create different neuropathic pain models to explore its effects.…”

Section: Effects Of Sting–ifn-i Pathway On Nociceptionmentioning

confidence: 99%

“…Short-term activation of this pathway led to transient and acute antinociception, which was maintained for up to 24 h ( Wang et al, 2021 ). However, consecutive and repeated administration of STING agonists caused central sensitization and nociception ( Wu et al, 2022 ). Fifth, the STING–IFN-I pathway does not participate in the physiological regulation of pain sensitivity and is only involved in the regulation of pain after nerve injury ( Sun et al, 2022 ; Wu et al, 2022 ).…”

Section: Effects Of Sting–ifn-i Pathway On Nociceptionmentioning

confidence: 99%

“…However, the antinociceptive effect was not substantial 11 days after the injection ( Wang et al, 2021 ). Similarly, activation of the STING–IFN-I pathway induces nociception or neuropathic pain at a late stage ( Liu et al, 2022 ; Wu et al, 2022 ). The exact effects of STING–IFN-I remain controversial, and its differential role in different sexes, neuropathic pain models, cells, and stages requires further research.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review

Yang

Shuai

Zhang

2023

Front. Mol. Neurosci.

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

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Section: Mechanism Of Sting–ifn-i Pathway With Respect To Painmentioning

confidence: 99%

Section: Effects Of Sting–ifn-i Pathway On Nociceptionmentioning

confidence: 99%

Section: Effects Of Sting–ifn-i Pathway On Nociceptionmentioning

confidence: 99%

Section: Effects Of Sting–ifn-i Pathway On Nociceptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review

Yang

Shuai

Zhang

2023

Front. Mol. Neurosci.

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TP53INP2 knockdown inhibits inflammatory response and apoptosis after spinal cord injury

Sun,

Chen,

Qin

2024

Immunity Inflam & Disease

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BackgroundSpinal cord injury (SCI) is a traumatic neurological disorder with limited therapeutic options. Tumor protein p53‐inducible nuclear protein 2 (TP53INP2) is involved in the occurrence and development of various diseases, and it may play a role during SCI via affecting inflammation and neuronal apoptosis. This study investigated the associated roles and mechanisms of TP53INP2 in SCI.MethodsMouse and lipopolysaccharide (LPS)‐induced SCI BV‐2 cell models were constructed to explore the role of TP53INP2 in SCI and the associated mechanisms. Histopathological evaluation of spinal cord tissue was detected by hematoxylin and eosin staining. The Basso, Beattie, and Bresnahan score was used to measure the motor function of the mice, while the spinal cord water content was used to assess spinal cord edema. The expression of TP53INP2 was measured using RT‐qPCR. In addition, inflammatory factors in the spinal cord tissue of SCI mice and LPS‐treated BV‐2 cells were measured using enzyme‐linked immunosorbent assay. Apoptosis and related protein expression levels were detected by flow cytometry and western blot analysis, respectively.ResultsTP53INP2 levels increased in SCI mice and LPS‐treated BV‐2 cells. The results of in vivo and in vitro experiments showed that TP53INP2 knockdown inhibited the inflammatory response and neuronal apoptosis in mouse spinal cord tissue or LPS‐induced BV‐2 cells.ConclusionsAfter spinal cord injury, TP53INP2 was upregulated, and TP53INP2 knockdown inhibited the inflammatory response and apoptosis.

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cGAS–STING, an important signaling pathway in diseases and their therapy

Li,

Wu,

et al. 2024

MedComm

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

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Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain

Cited by 35 publications

References 64 publications

Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review

Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review

TP53INP2 knockdown inhibits inflammatory response and apoptosis after spinal cord injury

cGAS–STING, an important signaling pathway in diseases and their therapy

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