Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain
Copyright © 2022 Elsevier Ltd. All rights reserved..
Neuroinflammation plays a vital role in the development of neuropathic pain and is mediated mainly by microglia. Suppressing microglial M1-polarization attenuates neuropathic pain. Recently, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a key mediator of inflammation and shows potential in modulating microglial polarization. In this study, we evaluated whether cGAS-STING is a potential therapeutic target. Spared nerve injury (SNI) surgery was conducted in adult male rats to establish a neuropathic pain model. We showed that SNI promoted microglial M1-polarization and induced cGAS-STING pathway activation in the spinal cord. Double-label immunofluorescence assays showed that cGAS-STING activation mainly occurred in neurons and microglia but not astrocytes. We further conducted in vitro experiments using BV-2 microglial cells. The results showed that LPS-induced microglial M1-polarization was accompanied by cGAS-STING pathway activation, but cGAS-STING inhibition by antagonists suppressed LPS-induced microglial M1-polarization. In vivo, we also showed that a cGAS antagonist and a STING antagonist suppressed the microglial M1-polarization and ameliorated the mechanical allodynia induced by SNI. These findings suggested that the cGAS-STING pathway might be a potential therapeutic target for treating neuropathic pain. However, further research is warranted to verify our findings in female rodents.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:217 |
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| Enthalten in: |
Neuropharmacology - 217(2022) vom: 01. Okt., Seite 109206 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wu, Wenyao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.08.2022 Date Revised 29.08.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.neuropharm.2022.109206 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Wu, Wenyao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain |
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| 520 | |a Copyright © 2022 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Neuroinflammation plays a vital role in the development of neuropathic pain and is mediated mainly by microglia. Suppressing microglial M1-polarization attenuates neuropathic pain. Recently, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a key mediator of inflammation and shows potential in modulating microglial polarization. In this study, we evaluated whether cGAS-STING is a potential therapeutic target. Spared nerve injury (SNI) surgery was conducted in adult male rats to establish a neuropathic pain model. We showed that SNI promoted microglial M1-polarization and induced cGAS-STING pathway activation in the spinal cord. Double-label immunofluorescence assays showed that cGAS-STING activation mainly occurred in neurons and microglia but not astrocytes. We further conducted in vitro experiments using BV-2 microglial cells. The results showed that LPS-induced microglial M1-polarization was accompanied by cGAS-STING pathway activation, but cGAS-STING inhibition by antagonists suppressed LPS-induced microglial M1-polarization. In vivo, we also showed that a cGAS antagonist and a STING antagonist suppressed the microglial M1-polarization and ameliorated the mechanical allodynia induced by SNI. These findings suggested that the cGAS-STING pathway might be a potential therapeutic target for treating neuropathic pain. However, further research is warranted to verify our findings in female rodents | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Microglia | |
| 650 | 4 | |a Neuropathic pain | |
| 650 | 4 | |a STING | |
| 650 | 4 | |a cGAS | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Sting1 protein, rat |2 NLM | |
| 650 | 7 | |a Cgas protein, rat |2 NLM | |
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| 700 | 1 | |a Zhang, Xianwei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shuo |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Tian |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Quanshui |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shiyong |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Wenlong |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Rao |e verfasserin |4 aut | |
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