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B Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression1
,¶
* Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
Department of Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany;
Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107;
Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia and British Columbia’s Children’s Hospital, Vancouver, British Columbia, Canada; and
¶ Division of Clinical Pharmacology, Department of Medicine, University of Munich, Munich, Germany
The IL-1 family cytokines are regulated on transcriptional and posttranscriptional levels. Pattern recognition and cytokine receptors control pro-IL-1β transcription whereas inflammasomes regulate the proteolytic processing of pro-IL-1β. 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-
B 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.
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 Institutes of Health Grants AI-065483 (to E.L.), AI-067497 (to K.A.F.), and AG14357 and AR055398 (to E.S.A.), a grant from the Dana Foundation (to E.L.), German Research Foundation Grant Ho2783/2-1 (to V.H.), and a grant from the Canadian Institutes for Health Research (to D.P.S.).
2 V.H. and E.L. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Eicke Latz, University of Massachusetts Medical School, Department of Infectious Diseases and Immunology, 364 Plantation Street, Lazare Research Building 308, Worcester, MA 01605. E-mail address: eicke.latz{at}umassmed.edu or Dr. Veit Hornung, University of Bonn, Department of Clinical Chemistry and Pharmacology, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. E-mail address: veit.hornung{at}uni-bonn.de
4 Abbreviations used in this paper: KO, knockout; IRAK4, IL-1R-associated kinase 4; MDP, muramyl dipeptide; TRIF, Toll/IL-1R domain-containing adapter inducing IFN-β; YFP, yellow fluorescent protein.
5 The online version of this article contains supplemental material.
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