| First Author | Chen R | Year | 2019 |
| Journal | Front Immunol | Volume | 10 |
| Pages | 1904 | PubMed ID | 31440260 |
| Mgi Jnum | J:285967 | Mgi Id | MGI:6400030 |
| Doi | 10.3389/fimmu.2019.01904 | Citation | Chen R, et al. (2019) AGER-Mediated Lipid Peroxidation Drives Caspase-11 Inflammasome Activation in Sepsis. Front Immunol 10:1904 |
| abstractText | 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 1beta 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 (Ager (Mye-/-)) 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. |
