HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900173v1 183/2/792    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by >Franchi, L. Articles by Núñez, G. PubMed PubMed Citation Articles by >Franchi, L. Articles by Núñez, G. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB SILICON DIOXIDE

TNF- Mediates Sensitization to ATP and Silica via the NLRP3 Inflammasome in the Absence of Microbial Stimulation

University of Michigan Medical School, Department of Pathology and Comprehensive Cancer Center, Ann Arbor, Michigan 48109

The Nlrp3 inflammasome is critical for the activation of caspase-1 in response to danger signals and particulate matter. However, its role in sterile inflammation remains unclear because prestimulation of phagocytic cells with microbial molecules is required for caspase-1 activation. We show here that exposure of macrophages and dendritic cells to TNF- promotes ATP- or silica-mediated caspase-1 activation and IL-1β secretion in the absence of microbial stimulation. The effect of TNF- was abolished in macrophages deficient in TNF receptor I and II, Nlrp3, or ASC, whereas that induced by TLR ligands required MyD88/Trif. In addition to TNF-, IL-1 and IL-1β promoted caspase-1 activation via Nlrp3 in response to ATP. Remarkably, macrophages tolerized to TNF-, but not to LPS, retained full sensitivity to ATP stimulation via Nlrp3. These results provide a mechanism by which danger signals and particulate matter mediate inflammation via the Nlrp3 inflammasome in the absence of microbial infection.

Address correspondence and reprint requests to Dr. Gabriel Núñez, Department of Pathology, University of Michigan Medical School, 4215 Cancer Center and Geriatrics Center Building, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: bclx{at}umich.edu.

This article has been cited by other articles:

				J. Harder, L. Franchi, R. Munoz-Planillo, J.-H. Park, T. Reimer, and G. Nunez Activation of the Nlrp3 Inflammasome by Streptococcus pyogenes Requires Streptolysin O and NF-{kappa}B Activation but Proceeds Independently of TLR Signaling and P2X7 Receptor J. Immunol., November 1, 2009; 183(9): 5823 - 5829. [Abstract] [Full Text] [PDF]