The inhibition of Kir2.1 potassium channels depolarizes spinal microglial cells, reduces their proliferation, and attenuates neuropathic pain

Glia ◽  
2020 ◽  
Vol 68 (10) ◽  
pp. 2119-2135 ◽  
Author(s):  
Christophe Gattlen ◽  
Alexandru‐Florian Deftu ◽  
Raquel Tonello ◽  
Yuejuan Ling ◽  
Temugin Berta ◽  
...  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Qi An ◽  
Chenyan Sun ◽  
Ruidi Li ◽  
Shuhui Chen ◽  
Xinpei Gu ◽  
...  

Abstract Background Calcitonin gene-related peptide (CGRP) as a mediator of microglial activation at the transcriptional level may facilitate nociceptive signaling. Trimethylation of H3 lysine 27 (H3K27me3) by enhancer of zeste homolog 2 (EZH2) is an epigenetic mark that regulates inflammatory-related gene expression after peripheral nerve injury. In this study, we explored the relationship between CGRP and H3K27me3 in microglial activation after nerve injury, and elucidated the underlying mechanisms in the pathogenesis of chronic neuropathic pain. Methods Microglial cells (BV2) were treated with CGRP and differentially enrichments of H3K27me3 on gene promoters were examined using ChIP-seq. A chronic constriction injury (CCI) rat model was used to evaluate the role of CGRP on microglial activation and EZH2/H3K27me3 signaling in CCI-induced neuropathic pain. Results Overexpressions of EZH2 and H3K27me3 were confirmed in spinal microglia of CCI rats by immunofluorescence. CGRP treatment induced the increased of H3K27me3 expression in the spinal dorsal horn and cultured microglial cells (BV2) through EZH2. ChIP-seq data indicated that CGRP significantly altered H3K27me3 enrichments on gene promoters in microglia following CGRP treatment, including 173 gaining H3K27me3 and 75 losing this mark, which mostly enriched in regulation of cell growth, phagosome, and inflammation. qRT-PCR verified expressions of representative candidate genes (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) and real-time cell analysis (RTCA) verified microglial proliferation. Additionally, CGRP treatment and CCI increased expressions of ITGAM, ADAM10, MCP-1, and CX3CR1, key mediators of microglial activation in spinal dorsal horn and cultured microglial cells. Such increased effects induced by CCI were suppressed by CGRP antagonist and EZH2 inhibitor, which were concurrently associated with the attenuated mechanical and thermal hyperalgesia in CCI rats. Conclusion Our findings highly indicate that CGRP is implicated in the genesis of neuropathic pain through regulating microglial activation via EZH2-mediated H3K27me3 in the spinal dorsal horn.


2017 ◽  
Vol 121 ◽  
pp. 49-59 ◽  
Author(s):  
Lorenzo Di Cesare Mannelli ◽  
Elena Lucarini ◽  
Laura Micheli ◽  
Ilaria Mosca ◽  
Paolo Ambrosino ◽  
...  

2013 ◽  
Vol 57 ◽  
pp. 1-9 ◽  
Author(s):  
Sarah L. Pollema-Mays ◽  
Maria Virginia Centeno ◽  
Crystle J. Ashford ◽  
A Vania Apkarian ◽  
Marco Martina

2012 ◽  
Vol 1451 ◽  
pp. 74-86 ◽  
Author(s):  
Kazuo Shibuta ◽  
Ikuko Suzuki ◽  
Masamichi Shinoda ◽  
Yoshiyuki Tsuboi ◽  
Kuniya Honda ◽  
...  

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Yajuan Li ◽  
Qingmin Li ◽  
Cunjuan Wang ◽  
Shengde Li ◽  
Lingzhi Yu

Neuropathic pain, which is one of the most common forms of chronic pain, seriously increases healthcare costs and impairs patients’ quality of life with an incidence of 7–10% worldwide. Microglia cell activation plays a key role in the progression of neuropathic pain. Better understanding of novel molecules modulating microglia cell activation and these underlying functions will extremely benefit the exploration of new treatment. Recent studies suggested long noncoding RNAs may be involved in neuropathic pain. However, its underlying functions and mechanisms in microglia cell activation remain unclear. To identify the differentially expressed lncRNAs and predict their functions in the progression of microglia cell activation, GSE103156 was analyzed using integrated bioinformatics methods. The expression levels of selected lncRNAs and mRNAs were determined by real-time PCR. In the present study, a total of 56 lncRNAs and 298 mRNAs were significantly differentially expressed. The differentially expressed mRNAs were mainly enriched in NF-kappa B signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and NOD-like receptor signaling pathway. The top 10 hub genes were Tnf, Il6, Stat1, Cxcl10, Il1b, Tlr2, Irf1, Ccl2, Irf7, and Ccl5 in the PPI network. Our results showed that Gm8989, Gm8979, and AV051173 may be involved in the progression of microglia cell activation. Taken together, our findings suggest that lots of lncRNAs may be involved in BV2 microglia cell activation in vitro. The findings may provide relevant information for the development of promising targets for the microglial cells activation of neuropathic pain in vivo in the future.


Pain ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 2605-2615 ◽  
Author(s):  
Xue-Feng Wu ◽  
Wen-Tao Liu ◽  
Yue-Peng Liu ◽  
Zhi-Jiang Huang ◽  
Yan-Kai Zhang ◽  
...  

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