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

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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01904

DOI=10.3389/fimmu.2019.01904

ISSN=1664-3224

ABSTRACT=<p>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 (<italic>Ager</italic><sup>−/−</sup>) or conditional depletion of <italic>AGER</italic> in myeloid cells (<italic>Ager</italic><sup><italic>Mye</italic>−/−</sup>) 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.</p>