title: Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β.
abstract: Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Man Lyang
authors.initials: ML
authors.lastname: Kim
authors.affiliation: Inflammatory Disease Section, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Chae
authors.affiliation: Inflammatory Disease Section, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yong Hwan
authors.initials: YH
authors.lastname: Park
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Dominic
authors.initials: D
authors.lastname: De Nardo
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Roslynn A
authors.initials: RA
authors.lastname: Stirzaker
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Hyun-Ja
authors.initials: HJ
authors.lastname: Ko
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Hazel
authors.initials: H
authors.lastname: Tye
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Cengia
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Ladina
authors.initials: L
authors.lastname: DiRago
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: Inflammatory Disease Section, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.affiliation: Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Dena
authors.initials: D
authors.lastname: Lyras
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.affiliation: Division of Inflammation, Division of Cancer and Hematology, Division of Immunology, and ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia masters@wehi.edu.au.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
mesh_terms: D000199:Actins / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004002:Clodronic Acid / Q000737:chemistry; D003433:Crosses, Genetic; D017077:Culture Media, Conditioned / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D056660:Hereditary Autoinflammatory Diseases / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000196:embryology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000166:cytology; D000071198:Pyrin; D015398:Signal Transduction
chemical_list: D000199:Actins; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008081:Liposomes; C000604192:MEFV protein, human; C000604193:Mefv protein, mouse; D008840:Microfilament Proteins; D000071198:Pyrin; C524014:Wdr1 protein, mouse; D004002:Clodronic Acid; D016173:Macrophage Colony-Stimulating Factor; D020169:Caspases; D020170:Caspase 1