Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKβ/NF-κB signaling pathway

Abstract

Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was widely recognized to be implicated in human cancer, vascular diseases, and neurological disorders. This study was to explore the role and underlying mechanism of MALAT1 in acute spinal cord injury (ASCI). ASCI models in adult rats were established and demonstrated by a numerical decrease in BBB scores. Expression profile of MALAT1 and miR-199b following ASCI in rats and in vitro was determined using quantitative real-time PCR. RNA pull-down assays combined with RIP assays were performed to explore the interaction between MALAT1 and miR-199b. In the present study, MALAT1 expression was significantly increased (2.4-fold that of control) in the spinal cord of the rat contusion epicenter accompanied by activation of IKKβ/NF-κB signaling pathway and an increase in the level of proinflammatory cytokines TNF-α and IL-1β. Upon treatment with LPS, MALAT1 expression dramatically increased in the microglia in vitro, but knockdown of MALAT1 attenuated LPS-induced activation of MGs and TNF-α and IL-1β production. Next, we confirmed that LPS-induced MALAT1 activated IKKβ/NF-κB signaling pathway and promoted the production of proinflammatory cytokines TNF-α and IL-1β through downregulating miR-199b. More importantly, MALAT1 knockdown gradually improved the hindlimb locomotor activity of ASCI rats as well as inhibited TNF-α, IL-1β levels, and Iba-1 protein, the marker of activated microglia in injured spinal cords. Our study demonstrated that MALAT1 was dysregulated in ASCI rats and in LPS-activated MGs, and MALAT1 knockdown was expected to attenuate ASCI through repressing inflammatory response of MGs.

Regulation of the Inflammatory Synovial Fibroblast Phenotype by Metastasis‐Associated Lung Adenocarcinoma Transcript 1 Long Noncoding RNA in Obese Patients With Osteoarthritis

“…In vivo, inflammation markers, including IL‐6, IL‐1β, TNF, and interferon‐γ, were all supressed in MALAT1‐knockout diabetic mice compared to wild‐type mice . Mechanistically, MALAT1 has recently been reported to bind to and modulate NF‐κB activity, thereby regulating the lipopolysaccharide‐induced inflammatory response .…”

Signatures of altered long noncoding RNAs and messenger RNAs expression in the early acute phase of spinal cord injury

“…In recent years, with the rapid development and widespread application of microarray, more and more researchers have found that many lncRNAs are involved in the development of SCI (Shi, Pan, & Feng, ). A recent study found that lncRNA MALAT1 expression was significantly increased (2.4‐fold that of control) in the contusion injured spinal cord of rats, and knockdown of MALAT1 was expected to attenuate SCI through inhibiting inflammatory response of microglial cells (H. J. Zhou et al, ). Furthermore, inhibition of lncRNA Sox2ot expression may protect PC‐12 cells from H 2 O 2 ‐induced injury in SCI by targeting the miR‐211/MCL‐1 isoform2 axis, and the Sox2ot‐miR‐211‐MCL‐1 isoform2 axis may be a promising therapeutic strategy for SCI (Yin et al, ).…”

Functional roles of lncRNAs and its potential mechanisms in neuropathic pain

“…Thus, further study can focus on how lncRNAs interact with immune pathways under pain condition. MALAT1 also contributes to the inflammatory response of microglia following SCI by modulating the miR-199b/IKKβ/NF-κB signaling pathway [68]. In conclusion, MALAT1 is closely related to the inflammatory reaction of microglia cells in a variety of pathological and physiological circumstances, such as brain injury and SCI described above.…”