Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
The IL-1 family cytokines are regulated on transcriptional and posttranscriptional levels. Pattern recognition and cytokine receptors control pro-IL-1beta transcription whereas inflammasomes regulate the proteolytic processing of pro-IL-1beta. The NLRP3 inflammasome, however, assembles in response to extracellular ATP, pore-forming toxins, or crystals only in the presence of proinflammatory stimuli. How the activation of gene transcription by signaling receptors enables NLRP3 activation remains elusive and controversial. In this study, we show that cell priming through multiple signaling receptors induces NLRP3 expression, which we identified to be a critical checkpoint for NLRP3 activation. Signals provided by NF-kappaB activators are necessary but not sufficient for NLRP3 activation, and a second stimulus such as ATP or crystal-induced damage is required for NLRP3 activation.
Bauernfeind
Franz G
FG
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Horvath
Gabor
G
Stutz
Andrea
A
Alnemri
Emad S
ES
MacDonald
Kelly
K
Speert
David
D
Fernandes-Alnemri
Teresa
T
Wu
Jianghong
J
Monks
Brian G
BG
Fitzgerald
Katherine A
KA
Hornung
Veit
V
Latz
Eicke
E
D000818:Animals; D017951:Antigen Presentation; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D016328:NF-kappa B / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018121:Receptors, Cytokine / Q000378:metabolism*; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
D002352:Carrier Proteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D018121:Receptors, Cytokine; D051192:Receptors, Pattern Recognition