Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome
Department of Medicine, Division of Infectious Disease & Immunology
Medical Subject Headings
Adaptor Proteins, Vesicular Transport; Animals; Carrier Proteins; Enzyme Activation; *Inflammasomes; Interferon-beta; Interleukin-1 Receptor-Associated Kinases; Listeria monocytogenes; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Receptors, Interleukin-1; Signal Transduction; Toll-Like Receptors
Immunity | Immunopathology
Activation of the NLRP3 inflammasome by diverse stimuli requires a priming signal from TLRs and an activation signal from purinergic receptors or pore-forming toxins. In this study, we demonstrate, through detailed analysis of NLRP3 activation in macrophages deficient in key downstream TLR signaling molecules, that MyD88 is required for an immediate early phase, whereas Toll/IL-1R domain-containing adapter inducing IFN-beta is required for a subsequent intermediate phase of posttranslational NLRP3 activation. Both IL-1R-associated kinase (IRAK) 1 and IRAK4 are critical for rapid activation of NLRP3 through the MyD88 pathway, but only IRAK1 is partially required in the Toll/IL-1R domain-containing adapter inducing IFN-beta pathway. IRAK1 and IRAK4 are also required for rapid activation of NLRP3 by Listeria monocytogenes, as deletion of IRAK1 or IRAK4 led to defective inflammasome activation. These findings define the pathways that lead to rapid NLRP3 activation and identify IRAK1 as a critical mediator of a transcription-independent,inflammasome-dependent early warning response to pathogenic infection.
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Citation: J Immunol. 2013 Oct 15;191(8):3995-9. doi: 10.4049/jimmunol.1301681. Epub 2013 Sep 16. Link to article on publisher's site
Fernandes-Alnemri, Teresa; Kang, Seokwon; Anderson, Connor; Sagara, Junji; Fitzgerald, Katherine A.; and Alnemri, Emad S., "Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome" (2013). University of Massachusetts Medical School Faculty Publications. 754.