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

D. Yang-Wei Fann, S. Y. Lee, S. Manzanero, S. C. Tang, M. Gelderblom, P. Chunduri, C. Bernreuther, M. Glatzel, Y. L. Cheng, J. Thundyil, A. Widiapradja, K. Z. Lok, S. L. Foo, Y. C. Wang, Y. I. Li, G. R. Drummond, M. Basta, T. Magnus, D. G. Jo, M. P. MattsonC. G. Sobey, T. V. Arumugam

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere790
JournalCell Death and Disease
Volume4
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

Fingerprint

Inflammasomes
Intravenous Immunoglobulins
Stroke
Brain
Reperfusion
Neurons
Interleukin-18
Interleukin-1
Cell Death
Theoretical Models
Ischemia
Therapeutics
Glucose
Middle Cerebral Artery Infarction
Brain Ischemia
Inbred C57BL Mouse

Keywords

  • Caspase
  • Cell death
  • Inflammasome
  • Ischemic stroke
  • IVIg

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

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

Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. / Yang-Wei Fann, D.; 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.

In: Cell Death and Disease, Vol. 4, No. 9, e790, 09.2013.

Research output: Contribution to journalArticle

Yang-Wei Fann, D, Lee, SY, Manzanero, S, Tang, SC, Gelderblom, M, Chunduri, P, Bernreuther, C, Glatzel, M, Cheng, YL, Thundyil, J, Widiapradja, A, Lok, KZ, Foo, SL, Wang, YC, Li, YI, Drummond, GR, Basta, M, Magnus, T, Jo, DG, Mattson, MP, Sobey, CG & Arumugam, TV 2013, 'Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke', Cell Death and Disease, vol. 4, no. 9, e790. https://doi.org/10.1038/cddis.2013.326
Yang-Wei Fann, D. ; 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. / Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. In: Cell Death and Disease. 2013 ; Vol. 4, No. 9.
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