The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation

• DOI: 10.1038/ni.2913
• Publication Date: 2014-06-22T18:06:40Z
• Authors: Bernardo S Franklin; Lukas Bossaller; Dominic De Nardo; Jacqueline M Ratter; Andrea Stutz; Gudrun Engels; Christoph Brenker; Mark Nordhoff; Sandra R Mirandola; Ashraf Al-Amoudi; Matthew S Mangan; Sebastian Zimmer; Brian G Monks; Martin Fricke; Reinhold E Schmidt; Terje Espevik; Bernadette Jones; Andrew G Jarnicki; Philip M Hansbro; Patricia Busto; Ann Marshak-Roths...; Simone Hornemann; Adriano Aguzzi; Wolfgang Kastenmü...; Eicke Latz
• Keywords: Inflammasomes; ASC specks; Interleukin-1beta; immunology [Signal Transduction]; Apoptosis; immunology [Phagocytosis]; Cell Communication; genetics [Carrier Proteins]; cytokine interleukin; Amino Acid Chloromethyl Ketones; immunology [Antibodies]; Mice; immunology [Inflammation]; genetics [Caspase 1]; adaptor ASC; immunology [Interleukin-1beta]; Mice, Knockout; Mice, Inbred BALB C; 0303 health sciences; pharmacology [Amino Acid Chloromethyl Ketones]; Caspase 1; cell-to-cell communication; immunology [Apoptosis]; immunology [Cytoskeletal Proteins]; immunology [Macrophages]; Caspase Inhibitors; immunology [Caspase 1]; 2723 Immunology and Allergy; immunology [Cell Communication]; 570; benzyloxycarbonyltyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; immunology [Pseudomonas Infections]; Prions; 10208 Institute of Neuropathology; Nlrp3 protein, mouse; 610 Medicine & health; pharmacology [Caspase Inhibitors]; immunology [Pseudomonas aeruginosa]; Antibodies; Autoimmune Diseases; 03 medical and health sciences; immunology [Autoimmune Diseases]; 616; NLR Family, Pyrin Domain-Containing 3 Protein; immunology [Autoantibodies]; Animals; Humans; ddc:610; genetics [Cytoskeletal Proteins]; Autoantibodies; Inflammation; 2403 Immunology; Macrophages; chemistry [Prions]; immunology [Inflammasomes]; Mice, Inbred C57BL; CARD Signaling Adaptor Proteins; Cytoskeletal Proteins; Pycard protein, mouse; inflammation; 570 Life sciences; biology; prionoid; Apoptosis Regulatory Proteins; Carrier Proteins; Lysosomes; pathology [Lysosomes]

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.