Novel Long Noncoding RNA, Macrophage Inflammation-Suppressing Transcript ( MIST ), Regulates Macrophage Activation During Obesity

Abstract

Objective: Systemic low-grade inflammation associated with obesity and metabolic syndrome is a strong risk factor for the development of diabetes mellitus and associated cardiovascular complications. This inflammatory state is caused by release of proinflammatory cytokines by macrophages, especially in adipose tissue. Long noncoding RNAs regulate macrophage activation and inflammatory gene networks, but their role in macrophage dysfunction during diet-induced obesity has been largely unexplored. Approach and Results: We sequenced total RNA from peritoneal macrophages isolated from mice fed either high-fat diet or standard diet and performed de novo transcriptome assembly to identify novel differentially expressed mRNAs and long noncoding RNAs. A top candidate long noncoding RNA, macrophage inflammation-suppressing transcript ( Mist ), was downregulated in both peritoneal macrophages and adipose tissue macrophages from high-fat diet–fed mice. GapmeR-mediated Mist knockdown in vitro and in vivo upregulated expression of genes associated with immune response and inflammation and increased modified LDL (low-density lipoprotein) uptake in macrophages. Conversely, Mist overexpression decreased basal and LPS (lipopolysaccharide)-induced expression of inflammatory response genes and decreased modified LDL uptake. RNA-pull down coupled with mass spectrometry showed that Mist interacts with PARP1 (poly [ADP]-ribose polymerase-1). Disruption of this RNA-protein interaction increased PARP1 recruitment and chromatin PARylation at promoters of inflammatory genes, resulting in increased gene expression. Furthermore, human orthologous MIST was also downregulated by proinflammatory stimuli, and its expression in human adipose tissue macrophages inversely correlated with obesity and insulin resistance. Conclusions: Mist is a novel protective long noncoding RNA, and its loss during obesity contributes to metabolic dysfunction and proinflammatory phenotype of macrophages via epigenetic mechanisms.

The Role of Inflammation in Diabetic Retinopathy

“…In another example, pyroptosis, a process involving activation of the inflammasome, is controlled by the lncRNA NEAT1 in diabetic nephropathy through the action of the mir34c/NLRP3 axis ( 73 ). Most recently, a novel lncRNA, macrophage inflammation-suppressing transcript ( 74 ) has been described which is lost in obese mice and is reduced in ATM from obese patients ( 75 ). In sum, visceral AT and its complement of inflammatory cells, especially ATMs, is a highly dynamic cellular structure under a wide variety of intrinsic and extrinsic epigenetic controls.…”

LncRNA VINAS regulates atherosclerosis by modulating NF-κB and MAPK signaling

“…Arterial inflammation occurs very early in atherogenesis and is associated with impairment of many salutary functions of the healthy endothelium. Accumulating studies point to lncRNAs as regulators of endothelial homeostasis, smooth muscle cell contractility, and macrophage-mediated inflammation in the vessel wall (11,13,(15)(16)(17)(18). This study provides evidence for the first time to our knowledge that the mouse-specific lncRNA VINAS and its human ortholog, DEPDC4, play important roles in vascular inflammation and atherogenesis.…”

Long Noncoding RNAs: Novel Important Players in Adipocyte Lipid Metabolism and Derivative Diseases

“…These studies have found several novel lncRNAs enriched in macrophages and differentially expressed in diet-induced mice models with obesity and early diabetes. For example, Stapleton et al (2020) found that MIST was associated with a macrophage anti-inflammatory phenotype during gain- and loss-of-function experiments. When transcription or interaction with RNAs of MIST was disrupted, expression of inflammatory genes heavily increased.…”