AGER-mediated lipid peroxidation drives caspase-11 inflammasome activation in sepsis

Ruochan Chen, Shan Zhu, Ling Zeng, Qingde Wang, Yi Sheng, Borong Zhou, Daolin Tang, Rui Kang

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Inflammasome activation can trigger an inflammatory and innate immune response through the release of cytokines and induction of pyroptosis. A dysfunctional inflammasome has been implicated in the development of human pathologies, including sepsis and septic shock. Here, we show that advanced glycosylation end-product specific receptor (AGER/RAGE) is required for caspase-11 inflammasome activation in macrophages. A nuclear damage-associated molecular pattern (nDAMP) complex, including high-mobility group box 1, histone, and DNA, can promote caspase-11-mediated gasdermin D cleavage, interleukin 1β proteolytic maturation, and lactate dehydrogenase release. The inhibition of AGER-mediated lipid peroxidation via arachidonate 5-lipoxygenase (ALOX5) limits caspase-11 inflammasome activation and pyroptosis in macrophages in response to nDAMPs or cytosolic lipopolysaccharide. Importantly, the pharmacologic inhibition of the AGER-ALOX5 pathway or global depletion (Ager−/−) or conditional depletion of AGER in myeloid cells (AgerMye−/−) protects against lipopolysaccharide-induced septic death in poly(I:C)-primed mice. These data identify a molecular basis for caspase-11 inflammasome activation and provide a potential strategy to treat sepsis.

Original languageEnglish (US)
Article number1904
JournalFrontiers in immunology
Issue numberAUG
StatePublished - 2019


  • AGER
  • ALOX5
  • Caspase-11
  • DAMP
  • Inflammasome
  • LPS
  • Lipid peroxidation
  • Sepsis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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