Functional delivery of lncRNA TUG1 by endothelial progenitor cells derived extracellular vesicles confers anti-inflammatory macrophage polarization in sepsis via impairing miR-9-5p-targeted SIRT1 inhibition

Wentao Ma,Lihua Xing,Mengying Yao,Qiuhong Liu,Hanbing Ning,Jing Gao,Weihong Zhang,Bing Cui

doi:10.1038/s41419-021-04117-5

Abstract

The delivery of biomolecules by extracellular vesicles (EVs) derived from endothelial progenitor cells (EPCs) has been proven to ameliorate sepsis, yet the therapeutic mechanism remains to be elucidated. Taurine upregulated gene 1 (TUG1) is a long noncoding RNA (lncRNA) that is downregulated in sepsis. The current study was designed to explore the role of EPCs derived EVs transmitting TUG1 in macrophage polarization and macrophage-mediated inflammation in a cecal ligation and puncture (CLP)-induced sepsis mouse model. TUG1 was underexpressed in CLP-induced sepsis, and its reexpression induced anti-inflammatory macrophage polarization and suppressed macrophage-medicated inflammatory injury to the pulmonary vascular endothelium. EPCs derived EVs transmitted TUG1 to promote M2 macrophage polarization. Luciferase, RIP, and RNA pull-down assays showed that TUG1 could competitively bind to microRNA-9-5p (miR-9-5p) to upregulate the expression of sirtuin 1 (SIRT1). Furthermore, EPCs derived EVs transmitted TUG1 to promote M2 macrophage polarization through the impairment of miR-9-5p-dependent SIRT1 inhibition. Finally, EPCs derived EVs carrying TUG1 were verified to ameliorate sepsis-induced organ damage in the murine model. In summary, EPCs derived EVs transmit TUG1 to attenuate sepsis via macrophage M2 polarization. This study also highlights the proinflammatory mechanism associated with miR-9-5p-mediated inhibition of SIRT1, which contributes to a more comprehensive understanding of the pathogenesis of sepsis.

Highlights

Sepsis is a dysfunctional systemic inflammatory disorder initiated by microbial infection, which frequently results in organ failure and mortality [1]
In view of the aforementioned literature, we aimed at substantiating whether extracellular vesicles (EVs) derived from endothelial progenitor cells (EPCs) can transmit long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) to protect against sepsis-induced inflammatory damage to the pulmonary vascular endothelium
We found that the expression of TUG1 was decreased in the septic mice receiving cecal ligation and puncture (CLP)

Summary

Introduction

Sepsis is a dysfunctional systemic inflammatory disorder initiated by microbial infection, which frequently results in organ failure and mortality [1]. We contend that molecular investigations focused on immune dysfunction should aid in the development of protective therapies against sepsis. EVs derived from the endothelial progenitor cells (EPCs) intensify the protective effects against sepsis-induced microvascular dysfunction [7]. Noncoding RNAs (ncRNAs) are a broad category of long noncoding RNA (lncRNAs) and microRNAs (miRs) that can be packaged in EVs and serve as specific biomarkers for the degree of acute kidney injury, especially sepsis [9, 10]. In view of the aforementioned literature, we aimed at substantiating whether EVs derived from EPCs can transmit lncRNA TUG1 to protect against sepsis-induced inflammatory damage to the pulmonary vascular endothelium

Methods

Results

Conclusion