https://scholars.lib.ntu.edu.tw/handle/123456789/467949
標題: | Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke | 作者: | Yang-Wei Fann D Lee S.-Y Manzanero S SUNG-CHUN TANG Gelderblom M Chunduri P Bernreuther C Glatzel M Cheng Y.-L Thundyil J Widiapradja A Lok K.-Z Foo S.L Wang Y.-C Li Y.-I Drummond G.R Basta M Magnus T Jo D.-G Mattson M.P Sobey C.G Arumugam T.V. |
公開日期: | 九月-2013 | 卷: | 4 | 期: | 9 | 起(迄)頁: | e790 | 摘要: | Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen-glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1β and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1β and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity. ? 2013 Macmillan Publishers Limited. All rights reserved. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/467949 | ISSN: | 2041-4889 | DOI: | 10.1038/cddis.2013.326 | SDG/關鍵字: | caspase 11; caspase 3; cryopyrin; glucose; immunoglobulin; inflammasome; interleukin 18; interleukin 1beta; interleukin 1beta converting enzyme; nucleotide binding oligomerization domain like receptor; nucleotide binding oligomerization domain like receptor 1; unclassified drug; X linked inhibitor of apoptosis; animal cell; animal experiment; animal model; article; brain cell; brain cell culture; brain damage; brain infarction size; brain ischemia; brain tissue; cell viability; controlled study; embryo; gene repression; human; human tissue; in vivo study; male; middle cerebral artery occlusion; mouse; nerve cell necrosis; neurologic examination; neuroprotection; nonhuman; oligomerization; priority journal; protein assembly; protein expression; protein targeting; reperfusion injury; stroke patient; Adaptor Proteins, Signal Transducing; Animals; Apoptosis Regulatory Proteins; Brain Ischemia; Carrier Proteins; Caspase 1; Caspase Inhibitors; Cell Death; Cells, Cultured; Cerebral Cortex; Cytoprotection; Disease Models, Animal; Humans; Immunoglobulins, Intravenous; Inflammasomes; Interleukin-18; Interleukin-1beta; Mice; Mice, Inbred C57BL; Neurons; Stroke; Treatment Outcome |
顯示於: | 醫學系 |
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