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 journalArticle

1 Citation (Scopus)

Abstract

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
Volume10
Issue numberAUG
DOIs
StatePublished - Jan 1 2019

Fingerprint

Inflammasomes
Caspases
Lipid Peroxidation
Sepsis
Lipopolysaccharides
Arachidonate 5-Lipoxygenase
Macrophage Activation
Human Development
Myeloid Cells
Septic Shock
Interleukin-1
L-Lactate Dehydrogenase
Innate Immunity
Histones
Macrophages
Drive
Pathology
Cytokines
DNA

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

AGER-mediated lipid peroxidation drives caspase-11 inflammasome activation in sepsis. / Chen, Ruochan; Zhu, Shan; Zeng, Ling; Wang, Qingde; Sheng, Yi; Zhou, Borong; Tang, Daolin; Kang, Rui.

In: Frontiers in immunology, Vol. 10, No. AUG, 1904, 01.01.2019.

Research output: Contribution to journalArticle

Chen, Ruochan ; Zhu, Shan ; Zeng, Ling ; Wang, Qingde ; Sheng, Yi ; Zhou, Borong ; Tang, Daolin ; Kang, Rui. / AGER-mediated lipid peroxidation drives caspase-11 inflammasome activation in sepsis. In: Frontiers in immunology. 2019 ; Vol. 10, No. AUG.
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