Frontiers in Immunology (Aug 2019)

AGER-Mediated Lipid Peroxidation Drives Caspase-11 Inflammasome Activation in Sepsis

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

DOI
https://doi.org/10.3389/fimmu.2019.01904
Journal volume & issue
Vol. 10

Abstract

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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.

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