The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages.
The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages.
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DOI：
10.1038/s41467-018-03409-3
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发表时间：
2018-03-08
影响因子：
16.6
通讯作者：
Stehlik C
中科院分区：
文献类型：
--
作者：
Chu LH;Indramohan M;Ratsimandresy RA;Gangopadhyay A;Morris EP;Monack DM;Dorfleutner A;Stehlik C
革兰氏阴性杆菌的脂多糖(LPS)可引起较强的免疫应答。尽管胞外内毒素是由TLR4在细胞表面感应并触发转录反应，但胞内内毒素结合并激活非典型炎症体caspase，导致焦性细胞死亡，以及典型的NLRP3炎症体依赖细胞因子的释放。与典型炎症小体激活caspase-1所需的高度调控的多蛋白平台相反，非典型小鼠caspase-11和同源人caspase-4同时作为固有的感受器和效应器发挥作用，它们的调控尚不清楚。在这里，我们发现氧化磷脂1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine(OxPAPC)抑制巨噬细胞中的非典型炎症体，但不抑制树突状细胞中的非典型炎症体。除了TLR4拮抗作用外，oxPAPC还直接与caspase-4和caspase-11结合，与内毒素结合竞争，从而抑制内毒素诱导的下垂、IL-1β的释放和感染性休克。因此，oxPAPC及其衍生物可能为针对革兰氏阴性细菌败血症期间的非典型性炎症体的治疗提供基础。非典型炎症体的激活在小鼠中由caspase-11介导，在人类中由caspase-4介导。在这里，作者表明，氧化1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine(OxPAPC)与脂多糖竞争结合这些半胱氨酸酶，在这样做的过程中，是巨噬细胞中非典型性炎症体激活的负调节因子，而不是树突状细胞中。
Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non-canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non-canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis. Non-canonical inflammasome activation is mediated by caspase-11 in mice and caspase-4 in humans. Here the authors show that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) competes with LPS for binding to these caspases and in so doing is a negative regulator of non-canonical inflammasome activation in macrophages, but not in dendritic cells.
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影响因子：
32.4
作者：
de Almeida L;Khare S;Misharin AV;Patel R;Ratsimandresy RA;Wallin MC;Perlman H;Greaves DR;Hoffman HM;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C
DOI：
10.4049/jimmunol.0802367
发表时间：
2009-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bryan NB;Dorfleutner A;Rojanasakul Y;Stehlik C
通讯作者：
Stehlik C
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.
影响因子：
3.8
作者：
Daro, E;Butz, E;McKenna, HJ
通讯作者：
McKenna, HJ
DOI：
10.1126/science.1240988
发表时间：
2013-09-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hagar JA;Powell DA;Aachoui Y;Ernst RK;Miao EA
通讯作者：
Miao EA