1. ASC has extracellular and prionoid activities that propagate inflammation
- Author
-
Franklin, Bernardo S., Bossaller, Lukas, De Nardo, Dominic, Ratter, Jacqueline M., Stutz, Andrea, Engels, Gudrun, Brenker, Christoph, Nordhoff, Mark, Mirandola, Sandra R., Al-Amoudi, Ashraf, Mangan, Matthew, Zimmer, Sebastian, Monks, Brian, Fricke, Martin, Schmidt, Reinhold E., Espevik, Terje, Jones, Bernadette, Jarnicki, Andrew G., Hansbro, Philip M., Busto, Patricia, Marshak-Rothstein, Ann, Hornemann, Simone, Aguzzi, Adriano, Kastenmüller, Wolfgang, and Latz, Eicke
- Subjects
endocrine system ,Inflammasomes ,Prions ,animal diseases ,Interleukin-1beta ,Apoptosis ,Cell Communication ,Article ,Antibodies ,Amino Acid Chloromethyl Ketones ,Autoimmune Diseases ,Mice ,Phagocytosis ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,Humans ,Pseudomonas Infections ,Autoantibodies ,Inflammation ,Mice, Knockout ,Mice, Inbred BALB C ,Macrophages ,Caspase 1 ,hemic and immune systems ,Caspase Inhibitors ,eye diseases ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,Cytoskeletal Proteins ,Pseudomonas aeruginosa ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Lysosomes ,tissues ,Signal Transduction - 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.
- Published
- 2014