Histones trigger sterile inflammation by activating the NLRP3 inflammasome
Histones trigger sterile inflammation by activating the NLRP3 inflammasome
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DOI：
10.1002/eji.201243224
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发表时间：
2013-12-01
影响因子：
5.4
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Allam, Ramanjaneyulu;Darisipudi, Murthy Narayana;Anders, Hans-Joachim
无菌细胞死亡介导的炎症与几种病理性疾病有关，涉及坏死细胞释放的细胞内分子的危险识别，这些分子激活不同组的先天模式识别受体。toll样受体直接与外源性或内源性激动剂相互作用，诱导多种促炎介质。相反，NLRP3炎症小体被认为是一个下游元件，将各种间接刺激整合到白细胞介素(IL)-1和IL-18的蛋白水解裂解中。在这里，我们报道了坏死细胞释放的组蛋白以nlrp3 - asc -caspase-1依赖的方式诱导IL-1分泌。小鼠NLRP3基因缺失显著减弱组蛋白诱导的IL-1产生和中性粒细胞募集。此外，坏死细胞诱导中性粒细胞募集，通过组蛋白中和抗体或通过酶降解消耗细胞外组蛋白可显著减少中性粒细胞募集。这些结果表明，坏死细胞源性组蛋白的胞质摄取是无菌炎症的触发机制，其中涉及NLRP3炎性体激活和IL-1通过氧化应激分泌。
Sterile cell death mediated inflammation is linked to several pathological disorders and involves danger recognition of intracellular molecules released by necrotic cells that activate different groups of innate pattern recognition receptors. Toll-like receptors directly interact with their extrinsic or intrinsic agonists and induce multiple proinflammatory mediators. In contrast, the NLRP3 inflammasome is rather thought to represent a downstream element integrating various indirect stimuli into proteolytic cleavage of interleukin (IL)-1 and IL-18. Here, we report that histones released from necrotic cells induce IL-1 secretion in an NLRP3-ASC-caspase-1-dependent manner. Genetic deletion of NLRP3 in mice significantly attenuated histone-induced IL-1 production and neutrophil recruitment. Furthermore, necrotic cells induced neutrophil recruitment, which was significantly reduced by histone-neutralizing antibodies or depleting extracellular histones via enzymatic degradation. These results identify cytosolic uptake of necrotic cell-derived histones as a triggering mechanism of sterile inflammation, which involves NLRP3 inflammasome activation and IL-1 secretion via oxidative stress.