Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway
- 28 November 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (50), 20054-20059
- https://doi.org/10.1073/pnas.1116302108
Abstract
We report here that mouse macrophages undergo receptor-interacting kinase-3 (RIP3)-dependent but TNF-α-independent necrosis when Toll-like receptors (TLR) 3 and 4 are activated by poly(I:C) and LPS, respectively. An adaptor protein, Toll/IL-1 receptor domain-containing adapter inducing IFN-β (TRIF/TICAM-1), which is dispensable for TNF-α-induced necrosis, forms a complex with RIP3 upon TLR3/TLR4 activation and is essential for TLR3/TLR4-induced necrosis. Mice without RIP3 or functional TRIF did not show macrophage loss and elevation of inflammatory cytokines when they were exposed to LPS. Necrosis in mouse macrophages induced by either TNFR or TLR3/TLR4 is executed by reactive oxygen species. Taken together, these data indicate that there are multiple upstream necrosis-initiating signaling pathways converging on the RIP3 during an innate immune response to viral and bacterial infections in mammals.Keywords
This publication has 31 references indexed in Scilit:
- cIAPs Block Ripoptosome Formation, a RIP1/Caspase-8 Containing Intracellular Cell Death Complex Differentially Regulated by cFLIP IsoformsMolecular Cell, 2011
- A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell DeathScience, 2004
- Functions of Toll-like receptors: lessons from KO miceComptes Rendus Biologies, 2004
- RIP1 is an essential mediator of Toll-like receptor 3–induced NF-κB activationNature Immunology, 2004
- A Role for Tumor Necrosis Factor Receptor-2 and Receptor-interacting Protein in Programmed Necrosis and Antiviral ResponsesOnline Journal of Public Health Informatics, 2003
- Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling PathwayScience, 2003
- Identification of Lps2 as a key transducer of MyD88-independent TIR signallingNature, 2003
- Caspase inhibition causes hyperacute tumor necrosis factor–induced shock via oxidative stress and phospholipase A2Nature Immunology, 2003
- Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3Nature, 2001
- The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB SignalImmunity, 1998