Byline: Yan-Hu. Liang, Guo-Wu. Chen, Xue-Song. Li, Shu. Jia, Chun-Yang. Meng
Several studies have confirmed that microglia are involved in neuropathic pain. Inhibition of guanosine-5'-triphosphate cyclohydrolase 1 (GTPCH1) can reduce the inflammation of microglia. However, the precise mechanism by which GTPCH1 regulates neuropathic pain remains unclear. In this study, BV2 microglia were transfected with adenovirus to knockdown GTPCH1 expression. High throughput sequencing analysis revealed that the mitogen-activated protein kinase (MAPK) related pathways and proteins were the most significantly down-regulated molecular function. Co-expression network analysis of Mapk14 mRNA and five long noncoding RNAs (lncRNAs) revealed their correlation. Quantitative reverse transcription-polymerase chain reaction revealed that among five lncRNAs, ENSMUST00000205634, ENSMUST00000218450 and ENSMUST00000156079 were related to the downregulation of Mapk14 mRNA expression. These provide some new potential targets for the involvement of GTPCH1 in neuropathic pain. This study is the first to note the differential expression of lncRNAs and mRNA in GTPCH1 knockdown BV2 microglia. Findings from this study reveal the mechanism by which GTPCH1 activates microglia and provide new potential targets for microglial activation in neuropathic pain.
Neuropathic pain (NP) is a common chronic disease affecting neurons. It causes significant impairments in the quality of life and a heavy economic burden on society (Colloca et al., 2017). The incidence of NP is 7-10% of the population worldwide (van Hecke et al., 2014; Alles and Smith, 2018). NP is mainly characterized by increased reactivity of nociceptive neurons in the peripheral and central nervous systems (Latremoliere and Woolf, 2009; Batista et al., 2019). The sensitivity of central and peripheral nervous systems to pain is caused by changes in the numerous functional proteins and signaling pathways of neurons and glial cells, such as microglia and astrocytes (LaCroix-Fralish et al., 2011). Although the pathogenesis of NP is unclear, microglial involvement in NP has been confirmed by many studies. Microglial cells participate in NP by releasing proinflammatory cytokines (Woolf, 2011; Inoue and Tsuda, 2018; Oh et al., 2020). They can also reduce neuronal apoptosis by reducing their release of pro-inflammatory cytokines (Rahimifard et al., 2017).
Guanosine-5'-triphosphate cyclohydrolase 1 (GTPCH1) is a member of the guanosine-5'-triphosphate cyclohydrolase family. The protein expressed by the GTPCH1 gene is a rate-limiting enzyme in the folic acid and biopterin biosynthetic pathways. It is responsible for the hydrolysis of guanosine triphosphate to form 7,8-dihydropterine triphosphate. GTPCH1 plays an important role in the pathogenesis of many diseases including NP (Tegeder et al., 2006; Young et al., 2012), Parkinson's disease (Terbeek et al., 2015) and tumors (Cronin et al., 2018). Though research has shown that inhibition of GTPCH1 can reduce the microglial inflammatory response, its specific mechanism of action is unclear.
Long noncoding RNA (lncRNA) is an important class of noncoding RNA whose transcription sequence has more than 200 nucleotides (Ponting et al., 2009). lncRNAs were originally thought to be a by-product of transcription. However, recent studies have found that they can be involved in gene expression by regulating transcription, post-transcriptional processing, chromatin remodeling and the production of small noncoding RNAs, among other processes...