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Cutting Edge: TNF- Mediates Sensitization to ATP and Silica via the NLRP3 Inflammasome in the Absence of Microbial Stimulation¹

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institute of Health Grants AI063331 and AI064748. L. Franchi was supported by a Fellowship from the Arthritis Foundation and T. Eigenbrod by a Fellowship from the Deutsche Forschungsgemeinschaft.

² 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

³ Abbreviations used in this paper: DC, dendritic cell; BMDM, bone marrow derived macrophage; CD40L, CD40 ligand; CHX, cycloheximide; NLR, Nod-like receptor; RANKL, receptor activator of NF-B ligand.

⁴ The online version of this article contains supplemental material.

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