The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China.
Front Immunol. 2019 Aug 8;10:1904. doi: 10.3389/fimmu.2019.01904. eCollection 2019.
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 () or conditional depletion of in myeloid cells () 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.
炎症小体的激活可以通过细胞因子的释放和细胞焦亡的诱导来触发炎症和先天免疫反应。功能失调的炎症小体与人类病理学的发展有关，包括败血症和感染性休克。在这里，我们表明，晚期糖基化终产物特异性受体（AGER/RAGE）是巨噬细胞中 caspase-11 炎症小体激活所必需的。核损伤相关分子模式（nDAMP）复合物，包括高迁移率族蛋白 B1、组蛋白和 DNA，可以促进 caspase-11 介导的 gasdermin D 切割、白细胞介素 1β 蛋白水解成熟和乳酸脱氢酶释放。通过花生四烯酸 5-脂氧合酶（ALOX5）抑制 AGER 介导的脂质过氧化作用，限制了 nDAMPs 或细胞溶质脂多糖诱导的巨噬细胞中 caspase-11 炎症小体的激活和细胞焦亡。重要的是，AGRE-ALOX5 途径的药理学抑制或骨髓细胞中 （）的全局耗竭或条件性耗竭（）可以防止聚（I:C）引发的小鼠脂多糖诱导的败血性死亡。这些数据确定了 caspase-11 炎症小体激活的分子基础，并为治疗败血症提供了一种潜在策略。
