Epigenetic reduction of miR-214-3p upregulates astrocytic colony-stimulating factor-1 and contributes to neuropathic pain induced by nerve injury

Abstract

Emerging evidence has indicated that colony-stimulating factor-1 (CSF1) modulates neuroinflammation in the central nervous system and the development of neuropathic pain, while the underlying mechanism remains unknown. Here, we identified the increased expression of CSF1 derived from activated astrocytes in the ipsilateral dorsal horn in rats with spinal nerve ligation (SNL). Suppression of CSF1 expression alleviated neuroinflammation, neuronal hyperexcitability, and glutamatergic receptor subunit upregulation in the dorsal horn and improved SNL-induced pain behavior. We also found reduced miR-214-3p expression in the ipsilateral dorsal horn following an SNL procedure; miR-214-3p directly bound to the 3′-UTR of CSF1 mRNA and negatively regulated CSF1 expression. Intrathecal delivery of miR-214-3p mimic reversed the enhanced expression of CSF1 and astrocyte overactivity and alleviated the IL-6 upregulation and pain behavior induced by SNL. Moreover, suppression of spinal miR-214-3p increased astrocyte reactivity, promoted CSF1 and IL-6 production, and induced pain hypersensitivity in naive animals. Furthermore, SNL induced the expression of DNA methyltransferase 3a (DNMT3a) that was associated with the hypermethylation of the miR-214-3p promoter, leading to reduced miR-214-3p expression in the model rodents. Treatment with the DNMT inhibitor zebularine significantly reduced cytosine methylation in the miR-214-3p promoter; this reduced methylation consequently increased the expression of miR-214-3p and decreased the content of CSF1 in the ipsilateral dorsal horn and, further, attenuated IL-6 production and pain behavior in rats with SNL. Together, our data indicate that the DNMT3a-mediated epigenetic suppression of miR-214-3p enhanced CSF1 production in astrocytes, which subsequently induced neuroinflammation and pain behavior in SNL model rats.

Plasma MicroRNA Expression Profiles in Psoriasis

“…In addition, stress can induce the interaction between mast cells and microglia and lead to inflammation [58], and inflammation of the [59]. miR-214-3p plays an important role in depressive-like behaviours, cognition defects, Alzheimer's disease, and endothelial cell dysfunction and mediates neural apoptosis, neuropathic pain, and the growth, migration, and invasion of glioma cells [60][61][62][63][64][65]. miR-7-5p is relevant to vascular endothelial cell proliferation, glioma, brain damage, and cognitive dysfunction [66][67][68][69].…”

Time course of DNA methylation in pain conditions: From experimental models to humans

“…Epigenetics‐based strategies for treatment of pain diseases are not yet available despite an increased focus on the topic (Niederberger et al., 2017). Research has already demonstrated the possibility of attenuating pain by DNA methylation modulation (Liu et al., 2020; Shao et al., 2017; Sun et al., 2015; Wang et al., 2011). At present, blockade of DNMTs has predominantly been investigated and it has been demonstrated to be the most effective way to prevent DNA hypermethylation (Cheng et al., 2019; Gnyszka et al., 2013).…”

“…Although these agents show great promise as potential future treatments for pain conditions (Liu et al., 2020; Shao et al., 2017; Sun et al., 2015; Wang et al., 2011), downsides also exist. In particular, common side effects of nucleoside analogues include genomic instability and mutagenic risk.…”

DNA Methylation and Non-Coding RNAs during Tissue-Injury Associated Pain

“…An up-regulation of DNMT3a2 has been found in the spinal cord of adult mice following CFA-injection, which was associated with the induction of Ptgs2 , a gene encoding for the pain-associated cyclooxygenase 2 enzyme (Cox-2) [ 27 ], as well as colony-stimulating factor-1 (CSF1), a secreted cytokine important for microglia activation following injury [ 24 ]. Intrathecal injections of recombinant adeno-associated viruses containing short hairpin RNAs targeting Dnmt3a2 mRNA led to reduced thermal and mechanical hypersensitivity during persistent pain states as assessed in the CFA model, while sparing acute inflammatory nociceptive responses [ 27 ].…”

“…DNMT3a has also been found to regulate gene expression. DNMT3a up-regulation has been detected in astrocytes of the rat spinal dorsal horn following SNL [ 24 ]. DNMT3a also appears to play an important role in the mouse amygdala, and that role might account for differences in pain vulnerability [ 25 ].…”