Regulation of the long noncoding RNA XIST on the inflammatory polarization of microglia in cerebral infarction

Abstract

Proinflammatory polarization of microglia aggravates brain injury in cerebral infarction. The present study focused on the role of long non-coding (lnc)RNA X-inactive specific transcript (XIST) in the phenotype modulation of microglia. It was revealed that lncRNA XIST was significantly upregulated in both a mouse cerebral infarction model induced by middle cerebral artery occlusion (MCAO) and an activated microglial model induced by oxygen/glucose deprivation (OGD). The overexpression of XIST enhanced the expression and release of pro-inflammatory mediators [such as tumor necrosis factor (TNF)-α, IL-6, and iNOS] in microglia. Culture supernatant from lncRNA XIST-overexpressed microglial cells induced the apoptosis of primary neurons, while TNF-α antibody counteracted this neurotoxic effect. LncRNA XIST served as a sponge for miR-96-5p, counteracting its inhibitory effect on IKKβ/NF-κB signaling and TNF-α production. Notably, TNF-α was positively regulated by XIST and in turn enhanced XIST expression in microglia. The lncRNA XIST-TNF-α feedback promoted the proinflammatory polarization of microglia, thereby exacerbating cerebral neuron apoptosis.

Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

“…In this review, the lncRNA/circRNA-miRNA-mRNA regulatory network also exists in microglia and astrocyte mediated neurological diseases, including SCI (Figure 1; Shao et al, 2020; FIGURE 1 | The lncRNA/circRNA-miRNA-mRNA regulatory network in microglia and astrocyte regulated neurological diseases. Xu S. et al, 2020;Zhao Q. et al, 2020;Cui et al, 2021;Xiang et al, 2021;Chen et al, 2022), TBI (He et al, 2021;Liu N. et al, 2021;Meng et al, 2021), cerebral IRI (Figure 1; Wang et al, 2020c;Yang et al, 2021), stroke (Figure 1; Qi et al, 2017;Han B. et al, 2018;Tian et al, 2021;Zhang M. et al, 2021), epilepsy (Figure 1; Feng et al, 2020;Han C. L. et al, 2020;Wan and Yang, 2020;Xiaoying et al, 2020), neuropathic pain (Figure 1; Chen M. et al, 2020), PD (Figure 1; Cao et al, 2018Cao et al, , 2021, and depression (Figure 1; . We also found that some therapies can impair the ncRNA-glial cell axis and thus inhibit disease development.…”

“…XIST serves as a sponge for miR-96-5p to antagonize inhibitory effects of miR-96-5p on the TNF-α expression. XIST up-regulation increases TNF-α expression through the miR-96-5p-IKKβ-NF-κB axis (Zhang M. et al, 2021). Moreover, TNF-α stimulation can increase XIST mRNA levels in BV2 cells.…”

“…Further, highly expressed SNHG14 can act as an induction effector of cerebral infarction severity (Qi et al, 2017). MiR-96-5p abrogates NF-κB signaling and TNF-α production via suppressing IKKβ expression in OGD-stimulated BV2 cells (Zhang M. et al, 2021). LncRNA XIST is highly expressed in BV2 cells exposed to OGD treatment.…”

“…Moreover, TNF-α stimulation can increase XIST mRNA levels in BV2 cells. The XIST-TNF-α feedback enhances the pro-inflammatory polarization of microglial cells, leading to exacerbating cerebral neuron apoptosis in cerebral infarction (Zhang M. et al, 2021).…”

Para‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

“…no. 20141012; Damao Chemical Reagent Factory) at a dose of 300 mg/kg weight (36). After routine disinfection, the following steps were undertaken: i) The skin was cut along the midline of the neck; ii) the muscle and fascia were separated layer by layer; iii) the vagus nerve was separated from the common carotid artery on the right; iv) the external carotid artery was ligated with nylon filament; and v) the middle cerebral artery was blocked by gently introducing 0.26-mm nylon filament (Ruibo Biotechnology Co., Ltd.) through the right common carotid artery.…”