Demethylase FTO promotes neuropathic pain development via regulating the m6A methylation levels of CXCR3

Abstract

Objective: Neuropathic pain (NPP) is an indirect or direct pain caused by somatic sensory nervous system dysfunction or primary injury, which is considered to be one of the most serious public health problems. This study aimed to investigate the role of adiposity-associated protein (FTO) in NPP. Materials and Methods: Sciatic nerve injury (SNI) treatment was performed to establish an NPP model in vivo. The qRT-PCR and western blot assays were conducted to measure the relative mRNA and protein expressions. Additionally, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of the mice were measured on days 0, 1, 3, 5, 7, and 14. The m6A level of CXCR3 was determined with Methylated RNA immunoprecipitation (MeRIP) assay and the inflammatory factor expressions were determined with Elisa kits. Results and Discussion: The FTO and CXCR3 expressions were up-regulated and the METTL14 expression was down-regulated in SNI mice. FTO-silenced increased the m6A and decreased the mRNA levels of CXCR3 in SNI mice. Furthermore, FTO-silenced decreased the mRNA stability of the CXCR3. Besides, in the SNI mice, FTO-silenced increased the PWL and PWT, and decreased the TNF-α, IL-1β, and IL-6 levels. While over-expressed CXCR3 inverted the FTO-silenced effects. Conclusions: Knockdown of FTO relieved the NPP progression via triggering the demethylation of CXCR3, thereby down-regulating the CXCR3expression.

Silencing of FTO inhibits oxidative stress to relieve neuropathic pain by m6A modification of GPR177

“…FTO functions as a demethylase to facilitate m6A modification of mRNA to promote NP. It was reported that FTO‐mediated m6A modification of G9a translates into NP symptoms 42 while knocking down FTO was found to relieve NP progression by promoting CXCR3 methylation 43 . Hence, the possible modification of RNA by FTO was investigated in this study.…”

“…It was reported that FTO‐mediated m6A modification of G9a translates into NP symptoms 42 while knocking down FTO was found to relieve NP progression by promoting CXCR3 methylation. 43 Hence, the possible modification of RNA by FTO was investigated in this study. NP is associated with abnormal neuronal activity often accompanied by abnormal expression of the WNT signaling pathway, transient receptor potential (TRP) family, and other key enzymes.…”

METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2

“…m6A hypomethylation of DNMT3B enhances its expression in the intervertebral discs and promotes low back pain (47). The demethylase FTO in the spinal dorsal horn promotes nociception by regulating m6A methylation of CXCR3 and increasing mRNA stability (48). Considering the role of the 3′-UTR in mRNA stability, we determined whether MET-TL14-mediated m6A modification affects Grin2a mRNA stability.…”