title: NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes.
abstract: Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer's disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPC-activated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance,Nlrc4-/-andNlrp3-/-mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.|Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Leslie
authors.initials: L
authors.lastname: Freeman
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Haitao
authors.identifier: 0000-0002-2737-2723
authors.initials: H
authors.lastname: Guo
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Clément N
authors.initials: CN
authors.lastname: David
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 jenny_ting@med.unc.edu sushmitajha@gmail.com.|Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Jha
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 jenny_ting@med.unc.edu sushmitajha@gmail.com.|Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.|Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.|Department of Microbiology and Immunology, Institute of Inflammatory Diseases, Center for Translational Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Jenny P-Y
authors.identifier: 0000-0002-7846-0395
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D003471:Cuprizone / Q000494:pharmacology; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000502:physiology*; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; D008244:Lysophosphatidylcholines; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D003471:Cuprizone