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

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.

Macrophage-derived miR-21 drives overwhelming glycolytic and inflammatory response during sepsis via repression of the PGE2/IL-10 axis

“…miR21 is one of the most abundant microRNAs expressed during LPS challenge, cytokine (TNF, IL1β, IL6, TGFβ, GM-CSF), and lipids (PGE2 and resolvin A1) stimulation (33). miR-21 is upregulated in septic patients and mice (Figure 1 and ( These findings also corroborated with Xue et al, that showed increased miR21 KO survival during sepsis by controlling IL1-dependent inflammasome activation (40). Delivery of a miR21…”

“…There is no common scientific consensus about the exact mechanism of miR-21 in the induction or repression of the inflammatory program. Several manuscripts suggest miR-21 as an anti-inflammatory target (41,(73)(74)(75), while others suggested this miRNA as a crucial proinflammatory factor (36,40,76). We observed an overall decrease in IL6 and IL1b and an increase in IL10 abundance in septic miR21∆myel when compared to septic WT mice.…”

The role of noncoding RNAs in epithelial cancer

“…Indeed, functional studies in several cancer cell lines demonstrated that knockdown of miR-21 activates caspases leading to apoptotic cell death. Moreover, in vitro evidence also suggested a positive regulatory role in pyroptosis through the activation of the NLRP3 inflammasome 83 . At a molecular level, miR-21 suppresses the expression of pro-apoptotic genes, such as APAF11, PDCD4, RHOB, and FASLG ( Fig.…”

Epigenetic Mechanisms of Inflammasome Regulation

“…A recent study investigated the role of this miRNA and demonstrated that miR-21 deficiency inhibited NLRP3, ASC and caspase-1 expressions. They found that knockout mice for miR-21 presented inhibited caspase-1 activation and IL-1β secretion [122]. Other studies elucidated the role of miR30e in inflammation.…”