MiR-21 promotes NLRP3 inflammasome activation to mediate pyroptosis and endotoxic shock

Zhenyi Xue,Hongkun Liu,Yan Li,Chao Gu,Guangze Yang,Zimu Zhang,Dongmei Zhou,Juhong Yang,Jieyou Zhang,Huiyun Yang,Yurong Da,Zhi Yao,Shuguang Duo,Xiangdong Guo,Lijuan Zhang,Qing Xi,Rongxin Zhang,Qi Zhang

doi:10.1038/s41419-019-1713-z

Abstract

miR-21 is aberrantly expressed, and plays a role in various types of tumors and many other diseases. However, the mechanism of miR-21 in LPS-induced septic shock is still unclear. In this study, we investigated the mechanism of miR-21 in LPS-induced pyroptosis and septic shock. Here, we show that miR-21 deficiency inhibited NLRP3, ASC, and caspase-1 expression, as well as inflammasome activation in myeloid cells from both mice and humans. We found that the NF-κB pathway was regulated by miR-21, and that A20 was a direct target of miR-21. Furthermore, miR-21 deficiency inhibited the ASC pyroptosome, which restrained caspase-1 activation and GSDMD cleavage, thereby preventing LPS-induced pyroptosis and septic shock. miR-21 deficiency resulted in an increase in A20, which led to decreased IL-1β production and caspase-1 activation. Caspase-1-mediated GSDMD cleavage was consequently decreased, which prevented pyroptosis in LPS-induced sepsis in mice. Our results demonstrate that miR-21 is a critical positive regulator of the NF-κB pathway and NLRP3 inflammasomes in pyroptosis and septic shock via A20. In addition, by analyzing published miRNA expression profiles in the Gene Expression Omnibus database, we found that the miR-21 levels in peripheral blood from patients with septic shock were elevated. Thus, miR-21 may serve as a potential treatment target in patients with septic shock.

Highlights

The nucleotide-binding domain, leucine-rich repeatcontaining receptor (NLR) family protein NLRP3 plays key roles in host defense, which can be activated by many pathogen-derived, environmental, and host-derived factors, including bacteria[1], viruses[2], fungi[3], components of dying cells[1], and crystal particles[4,5,6,7]
The increased reactivity of macrophages to inflammasomes was limited to NLRP3 inflammasomes because stimulation of AIM2 inflammasomes with dsDNA did not induce caspase-1 cleavage, IL-1β secretion, or pyroptosis in wild-type and miR-21−/− macrophages (Fig. 1i–k)
These data clearly indicate that miR-21 promotes IL-1β secretion and caspase-1 activation mediated by the NLRP3 inflammasome in mouse macrophages

Summary

Introduction

The nucleotide-binding domain, leucine-rich repeatcontaining receptor (NLR) family protein NLRP3 plays key roles in host defense, which can be activated by many pathogen-derived, environmental, and host-derived factors, including bacteria[1], viruses[2], fungi[3], components of dying cells[1], and crystal particles[4,5,6,7]. Xue et al Cell Death and Disease (2019)10:461 cleave gasdermin D (GSDMD), which is the core event in pyroptosis[16,17,18]. The role of GSDMD in pyroptosis is to trigger lethal sepsis and septic shock[18,19]. Deregulations of miRNA expression are well described, the pathophysiological role of miRNAs in septic shock has not yet been fully defined

Methods

Results

Conclusion