Cutting Edge: TNF-alpha Mediates Sensitization to ATP and Silica Via the NLRP3 Inflammasome in the Absence of Microbial Stimulation

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Jun 23

PMID 19542372

Citations 309

Authors

Luigi Franchi

Tatjana Eigenbrod

Gabriel Nunez

Affiliations

Soon will be listed here.

Abstract

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-alpha promotes ATP- or silica-mediated caspase-1 activation and IL-1beta secretion in the absence of microbial stimulation. The effect of TNF-alpha 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-alpha, IL-1alpha and IL-1beta promoted caspase-1 activation via Nlrp3 in response to ATP. Remarkably, macrophages tolerized to TNF-alpha, 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.

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