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

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-Rothstein; Simone Hornemann; Adriano Aguzzi; Wolfgang Kastenmüller; Eicke Latz

doi:10.1038/ni.2913

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

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

Authors

Bernardo S Franklin¹, Lukas Bossaller², Dominic De Nardo¹, Jacqueline M Ratter¹, Andrea Stutz¹, Gudrun Engels¹, Christoph Brenker³, Mark Nordhoff³, Sandra R Mirandola³, Ashraf Al-Amoudi³, Matthew S Mangan⁴, Sebastian Zimmer⁵, Brian G Monks⁶, Martin Fricke⁷, Reinhold E Schmidt⁷, Terje Espevik⁸, Bernadette Jones⁹, Andrew G Jarnicki⁹, Philip M Hansbro⁹, Patricia Busto¹⁰, Ann Marshak-Rothstein¹⁰, Simone Hornemann¹¹, Adriano Aguzzi¹¹, Wolfgang Kastenmüller¹², Eicke Latz¹³

Affiliations

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.

PMID: 24952505
PMCID: PMC4116676
DOI: 10.1038/ni.2913

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Chloromethyl Ketones / pharmacology
Animals
Antibodies / immunology
Apoptosis / immunology*
Apoptosis Regulatory Proteins
Autoantibodies / immunology
Autoimmune Diseases / immunology
CARD Signaling Adaptor Proteins
Carrier Proteins / genetics
Caspase 1 / genetics
Caspase 1 / immunology*
Caspase Inhibitors / pharmacology
Cell Communication / immunology
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / immunology*
Humans
Inflammasomes / immunology
Inflammation / immunology*
Interleukin-1beta / immunology*
Lysosomes / pathology
Macrophages / immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein
Phagocytosis / immunology
Prions / chemistry
Pseudomonas Infections / immunology
Pseudomonas aeruginosa / immunology
Signal Transduction / immunology

Substances

Amino Acid Chloromethyl Ketones
Antibodies
Apoptosis Regulatory Proteins
Autoantibodies
CARD Signaling Adaptor Proteins
Carrier Proteins
Caspase Inhibitors
Cytoskeletal Proteins
Inflammasomes
Interleukin-1beta
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Prions
Pycard protein, mouse
benzyloxycarbonyltyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone
Caspase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding