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CircMAPK1 induces cell pyroptosis in sepsis-induced lung injury by mediating KDM2B mRNA decay to epigenetically

Min Li1,2, Hanjing Lu2, Chujun Ruan1

  • 1Emergency Department of Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570311, Hainan Province, China.

Molecular Medicine (Cambridge, Mass.)
|September 19, 2024
PubMed
Abstract

Insights

Circular RNA MAPK1 (circMAPK1) exacerbates sepsis-induced lung injury by promoting macrophage pyroptosis. Silencing circMAPK1 protects against lung injury by stabilizing KDM2B mRNA and increasing WNK1 expression, thereby inhibiting the NLRP3 inflammasome.

Area of Science:

  • Molecular Biology
  • Immunology
  • Pathology

Background:

  • Macrophage pyroptosis is a key inflammatory process in sepsis-induced lung injury.
  • The precise molecular mechanisms driving this process remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of circular RNA MAPK1 (circMAPK1) in sepsis-induced lung injury.
  • To investigate the molecular mechanisms by which circMAPK1 influences macrophage pyroptosis and lung pathology.

Main Methods:

  • Established cell and mouse models of sepsis-induced lung injury.
  • Utilized qRT-PCR, Western blotting, IHC, ELISA, FISH, CCK-8, LDH assays, flow cytometry, ChIP, luciferase, RNA pull-down, RIP, and H&E staining to analyze molecular and pathological changes.
  • Investigated the interactions between circMAPK1, KDM2B, WNK1, and the NLRP3 inflammasome pathway.

Main Results:

  • CircMAPK1 levels were elevated in patients with septic lung injury.
  • Knockdown of circMAPK1 attenuated LPS/ATP-induced macrophage pyroptosis and improved cell viability via the WNK1/NLRP3 axis.
  • CircMAPK1 destabilizes KDM2B mRNA by recruiting UPF1, leading to decreased WNK1 expression and enhanced NLRP3-driven pyroptosis; silencing circMAPK1 reversed these effects and alleviated lung injury in mice.

Conclusions:

  • CircMAPK1 exacerbates sepsis-induced lung injury by promoting NLRP3-driven macrophage pyroptosis.
  • The mechanism involves circMAPK1 destabilizing KDM2B mRNA, suppressing WNK1 expression, and consequently activating the NLRP3 inflammasome.
  • Targeting circMAPK1 presents a potential therapeutic strategy for sepsis-induced lung injury.
Keywords:
CircMAPK1KDM2BMacrophage pyroptosisSepsisWNK1

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