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

Cell Death Dis. 2019 Jun 12;10(6):461. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism
  • Caspase 1 / metabolism
  • Cytokines / metabolism
  • Female
  • Humans
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipopolysaccharides
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / metabolism
  • Pyroptosis / drug effects
  • Pyroptosis / genetics*
  • Shock, Septic / chemically induced
  • Shock, Septic / genetics
  • Shock, Septic / metabolism*
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism

Substances

  • CARD Signaling Adaptor Proteins
  • Cytokines
  • Gsdmd protein, mouse
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • MIRN21 microRNA, human
  • MIRN21 microRNA, mouse
  • MicroRNAs
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Phosphate-Binding Proteins
  • Pycard protein, mouse
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tnfaip3 protein, mouse
  • Caspase 1