ASC has extracellular and prionoid activities that propagate inflammation

By B. S. Franklin, L. Bossaller, D. De Nardo, Jacqueline M. Ratter, A. Stutz, G. Engels, C. Brenker, M. Nordhoff, Sandra R. Mirandola, Ashraf Al-Amoudi and 15 more. Nature Immunology, 2014

726 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/66b06c49811bc20b458d127dad78780172fc75c6

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In Immunology

1. T. Kanneganti
2. F. Shao
3. Douglas R. Green
4. S. Bunnell
5. F. Sutterwala
6. S. Man
7. J. Wells
8. Olivier Julien

In Molecular Biology

1. T. Kanneganti
2. D. Sharma
3. S. Man
4. F. Shao
5. P. Boya
6. Eric I. Elliott
7. J. K. Kim
8. Douglas R. Green

Citations in the corpus

• Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, neutral): “RHO GTPase PYRIN Pyroptosis (237) ATP P2X7 Apoptosis (238, 239) ssRNA shRNA RIG-I Necroptosis Apoptosis (57, 240) dsDNA Genomic RNA DAI (DLM-1/ZBP) Necroptosis Apoptosis (56, 241) AIM2, absent in melanoma 2; DAI (DLM-1/ZBP), DNA-dependent activator of IFNregulatory factors; dsDNA, double stranded DN”
• Regulation of inflammasome activation (2015, background): “In addition, they are phagocytosed by neighboring macrophages and serve as an endogenous danger signal to trigger a second wave of inflammasome activation (194, 195).”
• An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “Moreover, recent findings suggest that ASC specks can be secreted or found ex vivo.(91,92) Further studies are needed to clarify how spatiotemporal coordination among intracellular organelles regulates the ASC secretion pathway and to decipher the complex interrelationships between ASC and other inf”
• The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis (2017, background): “It was revealed that extensive complexation aggravated inflammation by activating the production of inflammatory cytokines [7,8].”
• Lysosomal membrane permeabilization and cell death (2018, background): “whereby ASC-dependent endolysosomal damage gives rise to a sustained inflammatory response.(112) Moreover, endocytosis of highmobility group box 1 by macrophages induces cathepsin B release”
• Initiation and perpetuation of NLRP3 inflammasome activation and assembly (2015, background): “Given the fiber-like structure of ASC aggregates, it is also important to consider whether ASC might polymerize on cytoskeletal scaffolding (162, 165, 178).”
• The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation (2016, background): “This drives ASC nucleation, demonstrating the ability of specks to act as inflammasome-perpetuating signals in recipient cells (Baroja-Mazo et al., 2014; Franklin et al., 2014).”
• Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection (2018, background): “Our line of thinking is supported by reports that oligomerized ASC and the functional NLRP3 inflammasome can have extracellular activity (42).”