Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke

被引：507

作者：

Fann, D. Yang-Wei ^{[1
]}

Lee, S-Y ^{[1
]}

Manzanero, S. ^{[1
]}

Tang, S-C ^{[2
]}

Gelderblom, M. ^{[3
]}

Chunduri, P. ^{[1
]}

Bernreuther, C. ^{[4
]}

Glatzel, M. ^{[4
]}

Cheng, Y-L ^{[1
]}

Thundyil, J. ^{[1
]}

Widiapradja, A. ^{[1
]}

Lok, K-Z ^{[1
]}

Foo, S. L. ^{[1
]}

Wang, Y-C ^{[2
]}

Li, Y-I ^{[2
]}

Drummond, G. R. ^{[5
]}

Basta, M. ^{[6
]}

Magnus, T. ^{[3
]}

Jo, D-G ^{[7
]}

Mattson, M. P. ^{[8
]}

Sobey, C. G. ^{[5
]}

Arumugam, T. V. ^{[1
,7
,9
]}

机构：

[1] Univ Queensland, Sch Biomed Sci, St Lucia, Qld, Australia

[2] Natl Taiwan Univ Hosp, Stroke Ctr, Dept Neurol, Taipei, Taiwan

[3] Univ Clin Hamburg Eppendorf, Dept Neurol, Hamburg, Germany

[4] Univ Clin Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany

[5] Monash Univ, Dept Pharmacol, Clayton, Vic 3168, Australia

[6] Biovisions Inc, Potomac, MD USA

[7] Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea

[8] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA

[9] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117595, Singapore

来源：

CELL DEATH & DISEASE | 2013年 / 4卷

关键词：

IVIg; ischemic stroke; inflammasome; cell death; caspase; GLYCATION END-PRODUCTS; ANTHRAX LETHAL TOXIN; SPINAL-CORD-INJURY; CELL-DEATH; BRAIN-INJURY; CEREBRAL-ISCHEMIA; MOLECULAR PLATFORM; ACTIVATION; MECHANISMS; INHIBITION;

D O I：

10.1038/cddis.2013.326

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

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-1 beta and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1 beta 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.

引用

页码：e790 / e790

页数：10

共 53 条

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