Circular RNA circNrip1 Interacts with SYNCRIP to Promote Neuropathic Pain by Stabilizing Tlr2 mRNA in Primary Sensory Neurons

Nerve injury-induced gene dysregulation in the dorsal root ganglion (DRG) is considered a key molecular basis for neuropathic pain genesis. Circular RNA is emerging as a critical regulator of gene expression. Here, we reported a novel circular RNA circNrip1 formed by back-splicing from exon 3 to exon 2 of the Nrip1 pre-RNA. Peripheral nerve injury upregulates circNrip1, but not Nrip1 mRNA, in injured DRG neurons, at least in part due to increased binding of the RNA-binding protein FUS to Nrip1 pre-RNA, thereby promoting circNrip1 formation. Blocking this upregulation attenuates nerve injury-induced increases in toll-like receptor 2 (Tlr2) mRNA and TLR2 protein levels in injured DRG, as well as nerve injury-induced nociceptive hypersensitivity. Conversely, mimicking this upregulation elevates DRG Tlr2 mRNA and TLR2 protein expression and produces neuropathic pain-like symptoms in naïve mice. Mechanistically, upregulated circNrip1 enhances its binding to the 3'- untranslated region (UTR) of Tlr2 mRNA and to the RNA-binding protein SYNCRIP, thereby recruiting more SYNCRIP to the Tlr2 mRNA 3'-UTR and stabilizing Tlr2 mRNA in injured DRG neurons. Thus, circNrip1 contributes to neuropathic pain by promoting SYNCRIP-triggered stabilization of TLR2 in DRG neurons and represents a promising therapeutic target for intervention.