Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation

被引：245

作者：

Ives, Annette ^{[1
]}

Nomura, Johji ^{[1
,2
]}

Martinon, Fabio ^{[3
]}

Roger, Thierry ^{[4
]}

Leroy, Didier ^{[4
]}

Miner, Jeffrey N. ^{[5
]}

Simon, Gregoire ^{[1
]}

Busso, Nathalie ^{[1
]}

So, Alexander ^{[1
]}

机构：

[1] CHU Vaudois, Rheumatol Lab, CH-1011 Lausanne, Switzerland

[2] Teijin Pharma Ltd, Teijin Inst Bio Med Res, Pharmaceut Dev Res Labs, Tokyo 1918512, Japan

[3] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland

[4] CHU Vaudois, Infect Dis Lab, CH-1011 Lausanne, Switzerland

[5] Ardea Biosci, San Diego, CA 92121 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

瑞士国家科学基金会;

关键词：

URIC-ACID; NALP3; INFLAMMASOME; OXIDASE; ALLOPURINOL; DEHYDROGENASE; IDENTIFICATION; INHIBITOR; AUTOPHAGY; HYPERTENSION; CONVERSION;

D O I：

10.1038/ncomms7555

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Activation of the NLRP3 inflammasome by microbial ligands or tissue damage requires intracellular generation of reactive oxygen species (ROS). We present evidence that macrophage secretion of IL1 beta upon stimulation with ATP, crystals or LPS is mediated by a rapid increase in the activity of xanthine oxidase (XO), the oxidized form of xanthine dehydrogenase, resulting in the formation of uric acid as well as ROS. We show that XO-derived ROS, but not uric acid, is the trigger for IL1 beta release and that XO blockade results in impaired IL1 beta and caspase1 secretion. XO is localized to both cytoplasmic and mitochondrial compartments and acts upstream to the PI3K-AKT signalling pathway that results in mitochondrial ROS generation. This pathway represents a mechanism for regulating NLRP3 inflammasome activation that may have therapeutic implications in inflammatory diseases.

引用

页数：11

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