Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway

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.

[1]  G. Häcker,et al.  cIAPs Block Ripoptosome Formation, a RIP1/Caspase-8 Containing Intracellular Cell Death Complex Differentially Regulated by cFLIP Isoforms , 2011, Molecular cell.

[2]  T. Tenev,et al.  The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. , 2011, Molecular cell.

[3]  Guy S. Salvesen,et al.  Catalytic activity of the caspase-8-FLIPL complex inhibits RIPK3-dependent necrosis , 2011, Nature.

[4]  Joan W. Miller,et al.  Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis , 2010, Proceedings of the National Academy of Sciences.

[5]  P. Vandenabeele,et al.  Molecular mechanisms of necroptosis: an ordered cellular explosion , 2010, Nature Reviews Molecular Cell Biology.

[6]  L. O’Neill,et al.  New Insights into the Regulation of Signalling by Toll-Like Receptors and Nod-Like Receptors , 2010, Journal of Innate Immunity.

[7]  S. Akira,et al.  The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors , 2010, Nature Immunology.

[8]  W. Kaiser,et al.  Virus inhibition of RIP3-dependent necrosis. , 2010, Cell host & microbe.

[9]  Na Zhang,et al.  RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis , 2009, Science.

[10]  F. Chan,et al.  Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation , 2009, Cell.

[11]  Tao Wang,et al.  Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α , 2009, Cell.

[12]  T. Kawamoto,et al.  TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. , 2008, European journal of pharmacology.

[13]  Yide Mei,et al.  Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. , 2007, Cellular signalling.

[14]  You-Sun Kim,et al.  TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. , 2007, Molecular cell.

[15]  H. Osada,et al.  Inhibition of ADP/ATP Exchange in Receptor-Interacting Protein-Mediated Necrosis , 2006, Molecular and Cellular Biology.

[16]  R. Pope,et al.  NF-kappaB protects macrophages from lipopolysaccharide-induced cell death: the role of caspase 8 and receptor-interacting protein. , 2005, The Journal of biological chemistry.

[17]  Alexei Degterev,et al.  Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury , 2005, Nature chemical biology.

[18]  Xiaodong Wang,et al.  A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death , 2004, Science.

[19]  S. Akira,et al.  Functions of toll-like receptors: lessons from KO mice. , 2004, Comptes rendus biologies.

[20]  F. Martinon,et al.  RIP1 is an essential mediator of Toll-like receptor 3–induced NF-κB activation , 2004, Nature Immunology.

[21]  Xiaodong Wang,et al.  A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. , 2004, Science.

[22]  Kay Hofmann,et al.  RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. , 2004, Nature immunology.

[23]  B. Moss,et al.  A Role for Tumor Necrosis Factor Receptor-2 and Receptor-interacting Protein in Programmed Necrosis and Antiviral Responses* , 2003, Journal of Biological Chemistry.

[24]  Jiahuai Han,et al.  Identification of Lps2 as a key transducer of MyD88-independent TIR signalling , 2003, Nature.

[25]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[26]  P. Vandenabeele,et al.  Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA , 2002, Cell Death and Differentiation.

[27]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[28]  S. Akira,et al.  Unresponsiveness of MyD88-deficient mice to endotoxin. , 1999, Immunity.

[29]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[30]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[31]  Stefan Grimm,et al.  The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal , 1998 .

[32]  P. Leder,et al.  The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. , 1998, Immunity.