Targeted Inhibition of FTO Demethylase Protects Mice Against LPS-Induced Septic Shock by Suppressing NLRP3 Inflammasome.

Jiahui Luo,Shanjie Rong,Shu Zhang,Tiantian Yue,Fei Xiong,Qilin Yu,Faxi Wang,Chunliang Yang,Fei Sun,Jinxiu Li,Ping Yang,Qing Zhou,Cong-Yi Wang

doi:10.3389/fimmu.2021.663295

Abstract

Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N 6-methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto-siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock.

Highlights

There are more than 18 million cases of severe sepsis worldwide each year
We want to investigate whether Fat mass and obesity-related protein (FTO) expression and m6A level are related to the pathogenesis of sepsis in humans
LPS stimulation can decrease the expression of FTO in murine primary macrophages with significantly higher m6A level (Figures 1E–G)

Summary

Introduction

There are more than 18 million cases of severe sepsis worldwide each year. This disease refers to systemic inflammatory response syndrome caused by infections [1, 2]. NLRP3 inflammasome, causing the maturation and secretion of interleukin-1b (IL-1b), plays a critical role in the inflammatory response [5, 6]. The active NLRP3 inflammasome helps to recruit immune cells to the site of infection and trigger the adaptive immune response [7]. Under pathological conditions, the aberrant activation of NLRP3 inflammasome can lead to the occurrence of inflammatory diseases, including septic shock. Numerous studies have shown that NLRP3 inflammasomes are associated with lipopolysaccharide (LPS)-induced septic shock [8,9,10].

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Conclusion