title: AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3.
abstract: Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated speck-like protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, 1083, Hungary; Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and david.brough@manchester.ac.uk denesa@koki.hu.
authors.forename: Adam
authors.initials: A
authors.lastname: Denes
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Graham
authors.initials: G
authors.lastname: Coutts
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, 1083, Hungary;
authors.forename: Nikolett
authors.initials: N
authors.lastname: Lénárt
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Sheena M
authors.initials: SM
authors.lastname: Cruickshank
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and Inflammation and Experimental Surgery Unit, CIBERehd (Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas), Murcia Biohealth Research Institute-Arrixaca, University Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Pelegrin
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Joanne
authors.initials: J
authors.lastname: Skinner
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Nancy
authors.initials: N
authors.lastname: Rothwell
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and david.brough@manchester.ac.uk denesa@koki.hu.
authors.forename: David
authors.initials: D
authors.lastname: Brough
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism*; D002545:Brain Ischemia / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D007511:Ischemia / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017434:Protein Structure, Tertiary
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse
keywords: brain injury; cell death; cerebral ischemia; inflammasome; inflammation