STAT3‐activated lncRNA XIST accelerates the inflammatory response and apoptosis of LPS‐induced acute lung injury

Abstract

Acute lung injury (ALI) is a devastating respiratory disorder and severe clinical condition, which is characterized by the injury of alveolar epithelial cells and capillary endothelial cells. 1,2 ALI and its heavy form acute respiratory distress syndrome (ARDS) are a result of various situations, including pneumonia, trauma, sepsis, acute pancreatitis and so on. 3 In the ALI pathophysiological process, multiple factors are involved, including infiltration of inflammatory cells, proinflammatory mediator production and alveolar epithelial cell apoptosis. 4 Although significant advancements have been achieved, the annual mortality of ALI is still astonishing. 5 Examining the underlying mechanisms of ALI may provide a new approach to develop individualized therapeutic strategies and to investigate potential combination therapies for the ALI. Given the importance of targeted therapy, the ascertainment of accurate therapeutic targets is considered to be very critical.Long non-coding RNAs (lncRNAs) are the majority of transcripts generated from human genome. 6 The numerous transcripts without protein-coding potential have been discovered to play critical roles in multiple pathophysiological processes, including ALI. 7 For example, the knockdown of lncRNA MALAT1 exerts a protective role in the LPS-induced ALI rat model and inhibited LPS-induced inflammatory response in murine alveolar epithelial cells and murine alveolar macrophages cells through sponging miR-146a. 8 LncRNA H19 protects the LPS-mediated MRC-5 cell injury by inhibiting miR181, which in turn promotes the Runx2 expression to activate Notch and JNK pathways. 9 Collectively, the growing body of literature suggests that lncRNAs may remarkably regulate the pathophysiological process of ALI.

MiR‐146a‐5p accelerates sepsis through dendritic cell activation and glycolysis via targeting ATG7

“…[ 20 ] Additionally, studies have shown that mir‐146a‐5p can regulate AKT, STAT, and AMPK. [ 21–23 ] MiR‐146a‐5p is implicated with the imbalance of Th17/Treg induced by bone marrow mesenchymal stem cell‐derived exosomes via targeting IRAK1. [ 24 ] MiR‐146a‐5p targets TNF receptor‐related factor 6 to regulate the airway epithelial cell inflammatory response and injury.…”

XIST Regulates Breast Cancer Stem Cells by Activating Proinflammatory IL-6 Signaling

“…However, in post-XCI somatic tissues, dysregulation of XIST has recently been documented to play a role in chronic in ammatory diseases such as atherosclerosis [45], coronary artery disease[46], myocardial infarction [47], Alzheimer's disease[48], Parkinson disease [49], among others. Aberrant expression of XIST also promotes in ammatory responses during tissue injury such as cerebral ischemia/reperfusion injury [50], lipopolysaccharide (LPS)-induced acute lung injury (ALI) [51], and sepsis-induced acute liver injury [52]. In parallel with dysregulated XIST expression in post-XCI somatic tissues, aberrant expression of XIST in post-XCI BC cells is a common phenomenon implicated in therapeutic resistance by regulating breast CSCs [30][31][32].…”

“…XIST, by sponging/antagonizing miR-124, a STAT3 targeting miRNA, enhances STAT3 expression in retinoblastoma [64]. In LPS-induced ALI, XIST functions as a molecular sponge of miR-146a-5p positively regulating STAT3, which is then recruited to the promoter region of XIST to accelerate its transcription, thereby constituting a positive feedback loop that promotes in ammatory responses in ALI [51]. We suggest that this double positive feedback loop of XIST and STAT3 may contribute to the dysregulation of XIST in BC and other tumor types.…”

Extracellular Vesicles, New Players in Sepsis and Acute Respiratory Distress Syndrome

“…For example, Lnc-MALAT1 could sponge miR-149 ( Liang et al., 2019 ), miR-146a ( Dai et al., 2018 ) and miR-425 ( Wang et al., 2019 ) and Lnc-PRNCR1 could sponge miR-330-5p ( Yu et al., 2021 ). Lnc-SNHG5 could sponge miR-205 ( Wang J. et al., 2021 ) in LPS-induced ARDS model and Lnc-XIST can sponge miR-146a-5p ( Li J. et al., 2021 ). Lnc-TUG1 transmitted by EPC-derived EVs could bind to miR-9-5p, promote M2 macrophage polarization and ameliorate sepsis-induced organ damage ( Ma et al., 2021 ).…”