title: Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke.
abstract: Multi-protein complexes, termed "inflammasomes," are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-κB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-κB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-κB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9, Singapore, Singapore.
authors.forename: David Yang-Wei
authors.initials: DY
authors.lastname: Fann
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Yun-An
authors.initials: YA
authors.lastname: Lim
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9, Singapore, Singapore.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9, Singapore, Singapore.
authors.forename: Ker-Zhing
authors.initials: KZ
authors.lastname: Lok
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, 4072, Australia.
authors.forename: Prasad
authors.initials: P
authors.lastname: Chunduri
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Sang-Ha
authors.initials: SH
authors.lastname: Baik
authors.affiliation: Department of Pharmacology, Monash University, Clayton, VIC, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: Department of Anatomy, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: S Thameem
authors.initials: ST
authors.lastname: Dheen
authors.affiliation: Department of Pharmacology, Monash University, Clayton, VIC, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.|Memory Aging and Cognition Centre, National University Health System, Singapore, Singapore.
authors.forename: Christopher Li-Hsian
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9, Singapore, Singapore. phstva@nus.edu.sg.|School of Pharmacy, Sungkyunkwan University, Suwon, South Korea. phstva@nus.edu.sg.
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D048868:Adaptor Proteins, Signal Transducing; D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins; D002070:Butadienes; D007093:Imidazoles; D058847:Inflammasomes; C529636:NALP1 protein, mouse; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009570:Nitriles; D011725:Pyridines; D013450:Sulfones; C113580:U 0126; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; C093642:SB 203580
keywords: Inflammasome; Mitogen-activated protein kinases; NLRP; Neuronal cell death; Nuclear factor kappa B; Stroke