title: The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation.
abstract: Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adaptor ASC and the assembly of ASC specks. ASC specks recruit and activate caspase-1, which induces maturation of the cytokine interleukin 1β (IL-1β) and pyroptotic cell death. Here we found that after pyroptosis, ASC specks accumulated in the extracellular space, where they promoted further maturation of IL-1β. In addition, phagocytosis of ASC specks by macrophages induced lysosomal damage and nucleation of soluble ASC, as well as activation of IL-1β in recipient cells. ASC specks appeared in bodily fluids from inflamed tissues, and autoantibodies to ASC specks developed in patients and mice with autoimmune pathologies. Together these findings reveal extracellular functions of ASC specks and a previously unknown form of cell-to-cell communication.
authors: Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany.
authors: Bernardo S
authors: BS
authors: Franklin
authors: 1] Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany. [2] Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Lukas
authors: L
authors: Bossaller
authors: Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany.
authors: Dominic
authors: D
authors: De Nardo
authors: Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany.
authors: Jacqueline M
authors: JM
authors: Ratter
authors: Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany.
authors: Andrea
authors: A
authors: Stutz
authors: Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany.
authors: Gudrun
authors: G
authors: Engels
authors: German Center for Neurodegenerative Diseases, Bonn, Germany.
authors: Christoph
authors: C
authors: Brenker
authors: German Center for Neurodegenerative Diseases, Bonn, Germany.
authors: Mark
authors: M
authors: Nordhoff
authors: German Center for Neurodegenerative Diseases, Bonn, Germany.
authors: Sandra R
authors: SR
authors: Mirandola
authors: German Center for Neurodegenerative Diseases, Bonn, Germany.
authors: Ashraf
authors: A
authors: Al-Amoudi
authors: 1] Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany. [2] German Center for Neurodegenerative Diseases, Bonn, Germany.
authors: Matthew S
authors: MS
authors: Mangan
authors: Department of Medicine/Cardiology, University Hospitals, University of Bonn, Bonn, Germany.
authors: Sebastian
authors: S
authors: Zimmer
authors: 1] Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany. [2] Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Brian G
authors: BG
authors: Monks
authors: Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors: Martin
authors: M
authors: Fricke
authors: Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors: Reinhold E
authors: RE
authors: Schmidt
authors: Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors: Terje
authors: T
authors: Espevik
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, Newcastle, Australia.
authors: Bernadette
authors: B
authors: Jones
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, Newcastle, Australia.
authors: Andrew G
authors: AG
authors: Jarnicki
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, Newcastle, Australia.
authors: Philip M
authors: PM
authors: Hansbro
authors: Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Patricia
authors: P
authors: Busto
authors: Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Ann
authors: A
authors: Marshak-Rothstein
authors: University Hospital Zürich, Institute of Neuropathology, Zürich, Switzerland.
authors: Simone
authors: S
authors: Hornemann
authors: University Hospital Zürich, Institute of Neuropathology, Zürich, Switzerland.
authors: Adriano
authors: A
authors: Aguzzi
authors: Institute of Molecular Medicine and Experimental Immunology, University Hospitals, University of Bonn, Bonn, Germany.
authors: Wolfgang
authors: W
authors: Kastenmüller
authors: 1] Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany. [2] Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [3] German Center for Neurodegenerative Diseases, Bonn, Germany. [4] Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors: Eicke
authors: E
authors: Latz
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D002450:Cell Communication / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D008247:Lysosomes / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010587:Phagocytosis / Q000276:immunology; D011328:Prions / Q000737:chemistry; D011552:Pseudomonas Infections / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011328:Prions; C498534:Pycard protein, mouse; C460579:benzyloxycarbonyltyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; D020170:Caspase 1