Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

Peng, Yucong; Zhuang, Jianfeng; Ying, Guangyu; Zeng, Hanhai; Zhou, Hang; Cao, Yang; Chen, Huaijun; Xu, Chaoran; Fu, Xiongjie; Xu, Hangzhe; Li, Jianru; Cao, Shenglong; Chen, Jingyin; Gu, Chi; Yan, Feng; Chen, Gao

doi:10.1186/s12974-020-01830-4

Cited by 93 publications

(109 citation statements)

References 65 publications

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“…Recent studies indicated that activation of STING could promote microglial activation in several in ammatory models [53][54][55].The role of microglial activation in the development of SNI-induced neuropathic pain was corroborated by several pieces of evidence [30,56]. In our effort to clarify the mechanisms underlying microglia activation, we found that microglia and microglial response (including morphological change, proliferation, and release of mediators such as IL-1β, IL-6 and TNF-α) are essential for the induction of neuropathic pain after peripheral nerve injury [31].…”

Section: Discussionmentioning

confidence: 99%

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

Sun

Zhou

et al. 2021

Preprint

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Background Innate immune response acts as a first line of host defense against damage and are initiated following the recognition of pathogen-associated molecular patterns (PAMPs). For double-stranded DNA (dsDNA) sensing, interferon gene stimulator (STING) was discovered to be an integral sensor, and could mediate the immune and inflammatory response. However, it is unclear the underlying mechanisms of STING in the development of neuropathic pain. Methods Neuropathic pain model was established by spared nerve injury (SNI). STING agonist DMXAA was introduced into BV-2 cells to assess the inflammatory response in microglia cells. Selective STING antagonist C-176 were administered in the early and late stage following SNI and the mechanical sensitivity and thermal responsiveness were assessed using Von Frey filaments and hot plate tests separately. To investigate the underlying mechanisms, recombinant IL-6 was injected intrathecally and its downstream effectors were examined. The level of dsDNA in the peripheral blood following SNI was assessed using Elisa analysis. STING signaling pathway and its downstream effectors were assessed by qPCR, western blots, Elisa and immunofluorescence staining. Meanwhile, microglia activation and proinflammatory cytokines expression were also assessed in the spinal cord. Results We found dsDNA was significantly increased and STING signaling pathway was activated in dorsal horn microglia following SNI, and our study using BV-2 cells showed that DMXAA significantly activated STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway, and increased the production of proinflammatory cytokines, as well as phosphorylated the Janus-activated kinase 2/signal transducer activator of transcription 3 (JAK2/STAT3) signal in microglia. Early but not late intrathecal injection of C-176 attenuated SNI-induced pain hypersensitivity, microglia activation, proinflammatory factors and phosphorylated JAK2/STAT3 in the spinal cord dorsal horn. Last, the analgesic effect of C-176 were greatly abolished by recombinant IL-6 following SNI. Conclusions We provided evidence clarifying dsDNA mediated activation of microglial STING signaling pathway, after which promoting expression of proinflammatory cytokines that are required for central sensitization in the spinal cord dorsal horn of SNI model. Further analysis showed that microglial STING/TBK1/NF-κB may contribute to hyperalgesia initiation via IL-6/JAK2/STAT3 signaling. Pharmacological blockade of STING may be a promising target during the initiation of neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

Sun

Zhou

et al. 2021

Preprint

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“…SAH is a form of stroke often resulting from a ruptured aneurism or CNS injury ( Tenny and Thorell, 2020 ). Recently, Peng et al (2020) found increased STING and p-TBK1 protein expression 12 h post-injury in a mouse model of SAH. The administration of a STING agonist, CMA in SAH mice worsened the neuronal damage and neurobehavioral deficits when compared to vehicle-treated mice.…”

Section: Sting Activity In Acute Cns Pathologiesmentioning

confidence: 99%

“…The administration of a STING agonist, CMA in SAH mice worsened the neuronal damage and neurobehavioral deficits when compared to vehicle-treated mice. In contrast, administration of a small-molecule STING inhibitor C-176 shortly after SAH modelling conferred neuroprotection by reducing brain oedema, neuronal damage and attenuated the upregulation of pro-inflammatory microglial markers including IL-1β, iNOS and caspase-1 ( Peng et al, 2020 ). Upregulation of STING signalling has also been reported in rats 48–72 h after neonatal HI ( Gamdzyk et al, 2020 ).…”

Section: Sting Activity In Acute Cns Pathologiesmentioning

confidence: 99%

“…C-176 was shown by Haag et al (2018) to ablate STING activity through the blockade of activation-induced palmitoylation, impeding STING’s ability to translocate to the Golgi in response to CDN binding. Administration of C-176 intraperitoneally in SAH induced mice has also been shown to improve neurobehavioural outcomes and reduced the expression pro-inflammatory microglial markers including IL-1β, TNF-α and IL-6 ( Peng et al, 2020 ). Peng et al (2020) reported that inhibition of adenosine monophosphate-activated protein kinase (AMPK), a regulator of cellular energy homoeostasis ( Hardie, 2011 ) reversed the anti-inflammatory activity of C-176 in vitro and in vivo , suggesting that AMPK has a role in the inhibition of STING through C-176.…”

Section: Therapeutic Potential Of Targeting Stingmentioning

confidence: 99%

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The Complexity of the cGAS-STING Pathway in CNS Pathologies

Fryer

Abdullah

et al. 2021

Front. Neurosci.

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Neuroinflammation driven by type-I interferons in the CNS is well established to exacerbate the progression of many CNS pathologies both acute and chronic. The role of adaptor protein Stimulator of Interferon Genes (STING) is increasingly appreciated to instigate type-I IFN-mediated neuroinflammation. As an upstream regulator of type-I IFNs, STING modulation presents a novel therapeutic opportunity to mediate inflammation in the CNS. This review will detail the current knowledge of protective and detrimental STING activity in acute and chronic CNS pathologies and the current therapeutic avenues being explored.

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“…A Western blot analysis was performed as previously described [23]. Brie y, the basal ganglia were homogenized and centrifuged for 15 min (13,000 g, 4 °C).…”

Section: Western Blot Analysismentioning

confidence: 99%

Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

Chen

Zhou

et al. 2020

Preprint

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Background: Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH.Methods: ICH mouse models were established by the stereotactic injection of autologous arterial blood into the right basal ganglia. The selective RXR-α agonist bexarotene and peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist GW9662 were administered intraperitoneally at 1 h after ICH. Post-ICH assessments were in the form of magnetic resonance imaging scans, neurological tests, Western blotting, enzyme-linked immunosorbent assays, and immunofluorescence. Results: Pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in the microglia/macrophages, neurons, and astrocytes. Mechanically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, alongside reducing neuroinflammation by modulating microglia/macrophages reprograming into the M2 phenotype from M1 phenotype. However, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662.Conclusion: The pharmacological activation of RXR-α conferred robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.

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Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

Cited by 93 publications

References 65 publications

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

STING/NF-κB/IL-6-mediated inflammation in microglia contributes to spared nerve injury (SNI)-induced neuropathic pain

The Complexity of the cGAS-STING Pathway in CNS Pathologies

Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

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