Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation.
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.
Franchi
Luigi
L
University of Michigan Medical School, Department of Pathology and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
Eigenbrod
Tatjana
T
Núñez
Gabriel
G
D000255:Adenosine Triphosphate / Q000276:immunology*; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D003713:Dendritic Cells; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D052638:Particulate Matter / Q000276:immunology; D012822:Silicon Dioxide / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D052638:Particulate Matter; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide; D000255:Adenosine Triphosphate; D020170:Caspase 1