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

Fann, D. Yang-Wei, Lee, S-Y., Manzanero, S., Tang, S-C., 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. and Arumugam, T. V. (2013) Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death and Disease, 4 9: e790.1-e790.10. doi:10.1038/cddis.2013.326

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Author Fann, D. Yang-Wei
Lee, S-Y.
Manzanero, S.
Tang, S-C.
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.
Title Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke
Journal name Cell Death and Disease   Check publisher's open access policy
ISSN 2041-4889
Publication date 2013-09-01
Year available 2013
Sub-type Article (original research)
DOI 10.1038/cddis.2013.326
Open Access Status DOI
Volume 4
Issue 9
Start page e790.1
End page e790.10
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing
Language eng
Subject 2403 Immunology
2804 Cellular and Molecular Neuroscience
1307 Cell Biology
1306 Cancer Research
Abstract 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.
Keyword IVIg
Ischemic stroke
Cell death
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID FT100100427
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
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