Depression of lncRNA NEAT1 Antagonizes LPS-Evoked Acute Injury and Inflammatory Response in Alveolar Epithelial Cells via HMGB1-RAGE Signaling

Abstract

Sepsis-evoked acute lung injury (ALI) and its extreme manifestation, acute respiratory distress syndrome (ARDS), constitute a major cause of mortality in intensive care units. High levels of the long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) have been positively correlated with increased severity and unfavorable prognoses in patients with sepsis. Nevertheless, the function and molecular mechanism of NEAT1 in ALI remain elusive. In the current study, high levels of NEAT1 were confirmed in lipopolysaccharide- (LPS-) induced ALI mice models and in LPS-stimulated cells from the alveolar epithelial A549 cell line. Intriguingly, cessation of NEAT1 led to increased cell viability and decreased lactate dehydrogenase release, apoptosis, and caspase-3/9 activity, which conferred protection against LPS-induced injury in these cells. NEAT1 inhibition also restrained LPS-evoked transcripts and production of inflammatory cytokines IL-6, IL-1β, and TNF-α. A mechanism analysis corroborated the activation of high-mobility group box1 (HMGB1)/receptors for advanced glycation end products (RAGE) and NF-κB signaling in LPS-treated A549 cells. NEAT1 suppression reversed the activation of this pathway. Notably, reactivating HMGB1/RAGE signaling via HMGB1 overexpression blunted the anti-injury and anti-inflammation effects of NEAT1 knockdown. These findings suggest that NEAT1 may aggravate the progression of ALI and ARDS by inducing alveolar epithelial cell injury and inflammation via HMGB1/RAGE signaling, implying a promising treatment target for these conditions.

Long noncoding RNA NEAT 1 and its target microRNA‐125a in sepsis: Correlation with acute respiratory distress syndrome risk, biochemical indexes, disease severity, and 28‐day mortality

“…LncRNA NEAT1 is reported to be a critical regulator is the progression of sepsis. According to previous studies, the down‐regulation of lncRNA NEAT1 decreases several pro‐inflammatory cytokines by modulating let‐7a/TRL4 pathway, high‐mobility group box 1/receptors for advanced glycation end product (HMGB1/RAGE) pathway and NF‐κB pathway in sepsis cell model 11,13 . Meanwhile, inhibition of lncRNA NEAT1 alleviates cell apoptosis but promotes proliferation in sepsis‐evoked acute lung injury cell model 13 ; interestingly, similar results are also reported in sepsis‐induced acute kidney injury, myocardial injury, and brain injury cell models 10‐12 .…”

“…Possible explanations might be that (a) lncRNA NEAT1 high expression might modulate several signaling pathways (including the NF-κB pathway and HMGB1/RAGE pathway 11,13 ) to exacerbate inflammation and organ injury when the host was infected and (b) decreased promote inflammation and to suppress the clearance of invading microbiome of the immune system. 19,25 ARDS is one of the common complications of sepsis that might worsen the prognosis of sepsis patients.…”

“…In recent years, it is considered that lncRNA NEAT1 is highly involved in the regulation of sepsis. For instance, lncRNA NEAT1 could regulate several pathways including the nuclear factor‐κB (NF‐κB) pathway and toll‐like receptor 4 (TLR4) pathway to promote inflammation and injury of multiple organs such as liver, kidney, heart, and lung 10‐13 . Meanwhile, it is suggested that lncRNA NEAT1 might modulate the progression of sepsis through directly targeting microRNA (miR)‐125a, 14 and miR‐125a not only regulates inflammation in sepsis animal models, but also serves as a potential biomarker for the prediction of sepsis risk and the indication of inflammation, disease severity as well as the incidence of ARDS in sepsis patients 15,16 .…”

Long Non-Coding RNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) Represses Proliferation of Trophoblast Cells in Rats with Preeclampsia via the MicroRNA-373/FLT1 Axis

“…The present study found that knockdown of NEAT1 suppressed apoptosis, as evidenced by lower caspase-3 and caspase-9 activities, while increasing cell viability, migration, and invasion. Similarly, NEAT1 depletion enhanced the viability and reduced apoptosis and caspase-3/9 activities in alveolar epithelial cells challenged with lipopolysaccharide [ 19 ]. Moreover, NEAT1 potentiated the angiogenesis and survival of brain microvascular endothelial cells exposed to oxygen-glucose deprivation by targeting miR-377 [ 20 ].…”

LncRNA HOTAIR Increases Inflammatory Responses by Activating NF-κB Pathway in LPS-Induced Acute Lung Injury

“…LncRNAs were able to regulate varied genes expressed in cells and tissues [6]. It is reported that multiple lncRNAs have contribute to the progress of ALI, for example, high levels of the lncRNAs nuclear paraspeckle assembly transcript 1 (NEAT1) aggravated the progression of ALI via HMGB1/RAGE signaling, increased metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was positively correlated with increased severity and unfavorable prognoses via TSC2-mTOR and NF-κB signaling pathways [7] [8][9] [10]. Long noncoding RNA taurine up-regulated gene 1 (TUG1) targeted to miR-34b-5p and activated GRB2 associated binding protein 1 (GAB1), which showed a reducing pulmonary injury in ALI mice [11].…”