title: NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke.
abstract: Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1β (IL-1β) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Xinbing
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Xianfang
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Weichen
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Fengli
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xin
authors.affiliation: Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction; D020521:Stroke / Q000378:metabolism / Q000473:pathology*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D005947:Glucose; D010100:Oxygen