@ARTICLE{10.3389/fimmu.2019.01904, AUTHOR={Chen, Ruochan and Zhu, Shan and Zeng, Ling and Wang, Qingde and Sheng, Yi and Zhou, Borong and Tang, Daolin and 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/articles/10.3389/fimmu.2019.01904}, DOI={10.3389/fimmu.2019.01904}, ISSN={1664-3224}, 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.} }