title: Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway.
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.
authors: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, Suzhou 215123, China. hesudan@suda.edu.cn
authors: Sudan
authors: S
authors: He
authors: Yuqiong
authors: Y
authors: Liang
authors: Feng
authors: F
authors: Shao
authors: Xiaodong
authors: X
authors: Wang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C485615:Ripk3 protein, mouse