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.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: D Yang-Wei
authors.initials: DY
authors.lastname: Fann
authors.forename: S Y
authors.initials: SY
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Manzanero
authors.forename: S C
authors.initials: SC
authors.lastname: Tang
authors.forename: M
authors.initials: M
authors.lastname: Gelderblom
authors.forename: P
authors.initials: P
authors.lastname: Chunduri
authors.forename: C
authors.initials: C
authors.lastname: Bernreuther
authors.forename: M
authors.initials: M
authors.lastname: Glatzel
authors.forename: Y L
authors.initials: YL
authors.lastname: Cheng
authors.forename: J
authors.initials: J
authors.lastname: Thundyil
authors.forename: A
authors.initials: A
authors.lastname: Widiapradja
authors.forename: K Z
authors.initials: KZ
authors.lastname: Lok
authors.forename: S L
authors.initials: SL
authors.lastname: Foo
authors.forename: Y C
authors.initials: YC
authors.lastname: Wang
authors.forename: Y I
authors.initials: YI
authors.lastname: Li
authors.forename: G R
authors.initials: GR
authors.lastname: Drummond
authors.forename: M
authors.initials: M
authors.lastname: Basta
authors.forename: T
authors.initials: T
authors.lastname: Magnus
authors.forename: D G
authors.initials: DG
authors.lastname: Jo
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
authors.forename: C G
authors.initials: CG
authors.lastname: Sobey
authors.forename: T V
authors.initials: TV
authors.lastname: Arumugam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020521:Stroke / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D016756:Immunoglobulins, Intravenous; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D020170:Caspase 1