The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response

Alberto Baroja-Mazo; Fatima Martín-Sánchez; Ana I Gomez; Carlos M Martínez; Joaquín Amores-Iniesta; Vincent Compan; Maria Barberà-Cremades; Jordi Yagüe; Estibaliz Ruiz-Ortiz; Jordi Antón; Segundo Buján; Isabelle Couillin; David Brough; Juan I Arostegui; Pablo Pelegrín

doi:10.1038/ni.2919

The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response

Nat Immunol. 2014 Aug;15(8):738-48. doi: 10.1038/ni.2919. Epub 2014 Jun 22.

Authors

Affiliations

¹ 1] Inflammation and Experimental Surgery Unit, CIBERehd, Institute for Bio-Health Research of Murcia, Clinical University Hospital Virgen de la Arrixaca, Murcia, Spain. [2].
² Inflammation and Experimental Surgery Unit, CIBERehd, Institute for Bio-Health Research of Murcia, Clinical University Hospital Virgen de la Arrixaca, Murcia, Spain.
³ 1] Faculty of Life Sciences, University of Manchester, Manchester, UK. [2].
⁴ Department of Immunology-CDB, Hospital Clinic, Barcelona, Spain.
⁵ Reumathology Pediatric Unit, Hospital Sant Joan de Deu, Barcelona, Spain.
⁶ Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain.
⁷ Experimental and Molecular Immunology and Neurogenetics, CNRS UMR 7355, University of Orleans, Orleans, France.
⁸ Faculty of Life Sciences, University of Manchester, Manchester, UK.
⁹ 1] Inflammation and Experimental Surgery Unit, CIBERehd, Institute for Bio-Health Research of Murcia, Clinical University Hospital Virgen de la Arrixaca, Murcia, Spain. [2] Faculty of Life Sciences, University of Manchester, Manchester, UK.

PMID: 24952504
DOI: 10.1038/ni.2919

Abstract

Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin-associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins
CARD Signaling Adaptor Proteins
Carrier Proteins / blood
Carrier Proteins / genetics
Carrier Proteins / immunology*
Caspase 1 / genetics
Caspase 1 / immunology*
Caspases / genetics
Caspases / immunology
Caspases, Initiator
Cells, Cultured
Cryopyrin-Associated Periodic Syndromes / blood
Cytoskeletal Proteins / blood
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / immunology
HEK293 Cells
Humans
Inflammasomes / blood
Inflammasomes / immunology*
Inflammation / immunology*
Interleukin-1beta / blood
Interleukin-1beta / immunology
Macrophages / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein
Phagocytosis / immunology
Signal Transduction / immunology

Substances

Apoptosis Regulatory Proteins
CARD Signaling Adaptor Proteins
Carrier Proteins
Cytoskeletal Proteins
Inflammasomes
Interleukin-1beta
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
Nlrp3 protein, mouse
Pycard protein, mouse
Casp4 protein, mouse
Caspases
Caspases, Initiator
Caspase 1

Grants and funding

Wellcome Trust/United Kingdom