lncRNA GAS5‑mediated miR‑23a‑3p promotes inflammation and cell apoptosis by targeting TLR4 in a cell model of sepsis

Abstract

Sepsis is a syndrome characterized by organ dysfunction and an abnormal immune response to infection. A growing body of research has shown the importance of long non-coding RNAs (lncRNAs) in tumorigenesis, virus replication, inflammatory injury and other pathological processes. The aim of the present study was to explore the role and potential mechanism of the lncRNA growth arrest-specific 5 (GAS5) in the lipopolysaccharide (LPS)-induced inflammation and apoptosis of THP-1 cells. An in vitro sepsis model was established by treating THP-1 cells with LPS. Apoptosis was detected by flow cytometry. The expression levels of IL-6, IL-1β and TNF-α were detected using reverse transcription-quantitative PCR (RT-qPCR) and ELISA, and those of GAS5, microRNA (miR)-23a-3p and Toll-like receptor 4 (TLR4) were detected by RT-qPCR. The changes in the biological activity of THP-1 cells induced by the silencing of GAS5 and overexpression of miR-23a-3p and TLR4 were investigated. The relationships among GAS5, miR-23a-3p and TLR4 were analyzed using luciferase reporter assays. The results revealed that LPS increased the expression of GAS5 in THP-1 cells, and GAS5 knockdown effectively inhibited inflammation and cell apoptosis in the LPS-induced sepsis model. In addition, the results of the luciferase reporter assays indicated that both GAS5 and TLR4 directly target miR-23a-3p. The expression of miR-23a-3p was downregulated whereas that of TLR4 was upregulated in the septic cells. Further experiments showed that the overexpression of TLR4 attenuated the suppressive effects of miR-23a-3p overexpression and GAS5 knockdown on LPS-induced inflammation and apoptosis. In conclusion, the present study indicates that GAS5 strengthens LPS-induced inflammation and apoptosis via the miR-23a-3p/TLR4 pathway.

LncRNA GAS5 relates to Th17 cells and serves as a potential biomarker for sepsis inflammation, organ dysfunctions and mortality risk

“…Sepsis is featured by the extremely high mortality which is regarded as a global health priority by the WHO, therefore, it is urgent to find the biomarker involving the development and progression of sepsis to stratify the patients and individualize their treatment, which might help to improve the prognosis of sepsis patients 1–6 . Previous studies have reported the regulation role of lnc‐GAS5 in sepsis 18,24 . For instance, one study shows lnc‐GAS5‑mediated miR‑23a‑3p promotes inflammation and cell apoptosis by targeting TLR4 in a cell model of sepsis.…”

“…[1][2][3][4][5][6] Previous studies have reported the regulation role of lnc-GAS5 in sepsis. 18,24 For instance, one study shows lnc-GAS5-mediated miR-23a-3p pro- The lnc-GAS5 has been reported to be involved in regulating macrophage polarization, Treg cell differentiation, and inflammation in various inflammation-related diseases. For instance, in childhood pneumonia, lnc-GAS5 might regulate the Treg/Th17 imbalance by targeting the miR-217/STAT5 axis.…”

“… 1 , 2 , 3 , 4 , 5 , 6 Previous studies have reported the regulation role of lnc‐GAS5 in sepsis. 18 , 24 For instance, one study shows lnc‐GAS5‑mediated miR‑23a‑3p promotes inflammation and cell apoptosis by targeting TLR4 in a cell model of sepsis. Another study indicates that lnc‐GAS5 aggravates myocardial depression in mice with sepsis via the microRNA‐449b/HMGB1 axis and the NF‐κB signaling pathway.…”

“…However, with more comprehensive studies being performed, its anti‐inflammation role has been proposed. Recent studies disclose that lnc‐GAS5 inhibits the differentiation of T cells into Th17 cells, macrophage M1 polarization while promotes macrophage M2 polarization, and restrains the inflammation as well as sepsis‐induced organ injury in multi‐complex diseases, which implies that it might be engaged in the pathogenesis of sepsis 15–21 . Nevertheless, the clinical involvement of lnc‐GAS5 in sepsis remains unclear.…”

“…Recent studies disclose that lnc‐GAS5 inhibits the differentiation of T cells into Th17 cells, macrophage M1 polarization while promotes macrophage M2 polarization, and restrains the inflammation as well as sepsis‐induced organ injury in multi‐complex diseases, which implies that it might be engaged in the pathogenesis of sepsis. 15 , 16 , 17 , 18 , 19 , 20 , 21 Nevertheless, the clinical involvement of lnc‐GAS5 in sepsis remains unclear. Hence, this study aimed to further evaluate its linkage with Th1 cells and Th17 cells, as well as its clinical value in sepsis management.…”