Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome
Authors
Fernandes-Alnemri, TeresaKang, Seokwon
Anderson, Connor
Sagara, Junji
Fitzgerald, Katherine A.
Alnemri, Emad S.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Disease & ImmunologyDocument Type
Journal ArticlePublication Date
2013-10-15Keywords
Adaptor Proteins, Vesicular TransportAnimals
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
Metadata
Show full item recordAbstract
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.Source
J Immunol. 2013 Oct 15;191(8):3995-9. doi: 10.4049/jimmunol.1301681. Epub 2013 Sep 16. Link to article on publisher's siteDOI
10.4049/jimmunol.1301681Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30478PubMed ID
24043892Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.1301681