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Nat Immunol. 2014 Aug;15(8):727-37. doi: 10.1038/ni.2913. Epub 2014 Jun 22.

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

Author information

1
Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany.
2
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.
3
German Center for Neurodegenerative Diseases, Bonn, Germany.
4
1] Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn, Germany. [2] German Center for Neurodegenerative Diseases, Bonn, Germany.
5
Department of Medicine/Cardiology, University Hospitals, University of Bonn, Bonn, Germany.
6
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.
7
Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
8
Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
9
Centre for Asthma and Respiratory Disease, The University of Newcastle, Newcastle, Australia.
10
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
11
University Hospital Zürich, Institute of Neuropathology, Zürich, Switzerland.
12
Institute of Molecular Medicine and Experimental Immunology, University Hospitals, University of Bonn, Bonn, Germany.
13
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.

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.

PMID:
24952505
PMCID:
PMC4116676
DOI:
10.1038/ni.2913
[Indexed for MEDLINE]
Free PMC Article

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