Inhibition of SIRT1 by microRNA-9, the key point in process of LPS-induced severe inflammation

Abstract

Severe inflammation may lead to multiple organs dysfunction syndrome, which has a high mortality. MicroRNA is found participated in this process. In this study we developed a lipopolysaccharide-induced inflammation cell model on macrophages and a lipopolysaccharide-induced inflammation mouse model. It was found that during inflammation, microRNA-9 was increased, accompanied with the up-regulation of pro-inflammatory cytokines and anti-inflammatory cytokines. Down-regulation of microRNA-9 inhibited the up-regulation of inflammatory cytokines, promoted the up-regulation of anti-inflammatory cytokines and induced the remission of organ damage, showing a protective effect in inflammation. Bioinformatics analysis combined with luciferase reporter assay showed that SIRT1 was the target gene of microRNA-9. Transfection of microRNA-9 inhibitor could increase the level of SIRT1 and decrease the activation of NF-κB pathway in macrophages. Myeloid specific sirt1 knockout mice were included and we found that lack of SIRT1 in mice macrophages led to aggravated inflammation, cell apoptosis and organ injury, and eliminated the protective property of microRNA-9 inhibitor. In conclusion, we demonstrated that inhibition of microRNA-9 could alleviate inflammation through the up-regulation of SIRT1 and then suppressed the activation of NF-κB pathway. This is a meaningful explore about the specific mechanism of microRNA-9 in inflammation.

MicroRNA-9 Fine-Tunes Dendritic Cell Function by Suppressing Negative Regulators in a Cell-Type-Specific Manner

“…miR-9 has been previously shown to specifically target Sirt1 in macrophages, preventing Sirt1 from S1. 31, 107585, May 5, 2020 11 Article ll OPEN ACCESS deacetylating and inhibiting NF-kB, possibly leading to a feedforward loop, increasing miR-9 expression (Cao et al, 2018). Other studies have linked miR-9 with regulation of the chromatin landscape in neural progenitors through its action on Rest, and its corepressor Rcor1, which were also regulated by miR-9 in DCs (Packer et al, 2008;Delaloy et al, 2010).…”

“…The expression of miR-9 is dynamic and has been observed to be upregulated in human monocytes and neutrophils when stimulated with LPS (Bazzoni et al, 2009;Lu et al, 2019;Thulin et al, 2013). In macrophages, inhibition of miR-9 leads to a reduction of organ damage in a model of severe LPS-induced inflammation (Cao et al, 2018). Specifically in DCs, microRNA profiling of activated human DCs revealed that miR-9 is upregulated upon LPS stimulation (Stumpfova et al, 2014).…”

MCPIP1 alleviated lipopolysaccharide‐induced liver injury by regulating SIRT1 via modulation of microRNA‐9

“…It was reported that SIRT1 to be a target of miR-9 (Bu et al, 2017;Cao et al, 2018;D'Adamo et al, 2017). To confirm that miR-9 could target SIRT1 in mouse-derived RAW 264.7 macrophages, we used TargetScan browser to predict the binding site of SIRT1 and miR-9.…”

“…Together, these results demonstrated that miR-9 was negatively regulated by MCPIP1 and overexpression of miR-9 reversed MCPIP1-mediated inflammatory response. It was reported that SIRT1 to be a target of miR-9 (Bu et al, 2017;Cao et al, 2018;D'Adamo et al, 2017). To confirm that miR-9 could target SIRT1 in mouse-derived RAW 264.7 macrophages, we used TargetScan browser to predict the binding site of SIRT1 and miR-9.…”

Analysis of microRNA expression profiles in porcine PBMCs after LPS stimulation

“… 8 MiR-9 increased LPS-induced inflammatory response of macrophages by targeting silent information regulator 1 (SIRT1). 9 Moreover, a number of miRNAs regulate elements of the TLR-signalling cascade or target cytokines directly. MiR-146b directly targets IL-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6), key adaptor proteins of the TLR4/NF-κB signalling cascade, resulting in inhibition of NF-κB activation and inflammatory cytokine production.…”