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. Mattson; C. G. Sobey; T. V. Arumugam

doi:10.1038/cddis.2013.326

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 journal › Article › peer-review

243 Scopus citations

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 language	English (US)
Article number	e790
Journal	Cell Death and Disease
Volume	4
Issue number	9
DOIs	https://doi.org/10.1038/cddis.2013.326
State	Published - Sep 2013
Externally published	Yes

Keywords

Caspase
Cell death
Inflammasome
Ischemic stroke
IVIg

ASJC Scopus subject areas

Cell Biology
Immunology
Cancer Research
Cellular and Molecular Neuroscience

Access to Document

10.1038/cddis.2013.326

Cite this

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., ... Arumugam, T. V. (2013). Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death and Disease, 4(9), Article e790. https://doi.org/10.1038/cddis.2013.326

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

@article{db5976217df94f7b918466effd68ba82,

title = "Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke",

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.",

keywords = "Caspase, Cell death, Inflammasome, Ischemic stroke, IVIg",

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

year = "2013",

month = sep,

doi = "10.1038/cddis.2013.326",

language = "English (US)",

volume = "4",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke

AU - Yang-Wei Fann, D.

AU - Lee, S. Y.

AU - Manzanero, S.

AU - Tang, S. C.

AU - Gelderblom, M.

AU - Chunduri, P.

AU - Bernreuther, C.

AU - Glatzel, M.

AU - Cheng, Y. L.

AU - Thundyil, J.

AU - Widiapradja, A.

AU - Lok, K. Z.

AU - Foo, S. L.

AU - Wang, Y. C.

AU - Li, Y. I.

AU - Drummond, G. R.

AU - Basta, M.

AU - Magnus, T.

AU - Jo, D. G.

AU - Mattson, M. P.

AU - Sobey, C. G.

AU - Arumugam, T. V.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Caspase

KW - Cell death

KW - Inflammasome

KW - Ischemic stroke

KW - IVIg

UR - http://www.scopus.com/inward/record.url?scp=84884993094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884993094&partnerID=8YFLogxK

U2 - 10.1038/cddis.2013.326

DO - 10.1038/cddis.2013.326

M3 - Article

C2 - 24008734

AN - SCOPUS:84884993094

SN - 2041-4889

VL - 4

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 9

M1 - e790

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this